Amino acid derivatives and drugs containing the same as the active ingredient

ABSTRACT

The present invention relates to the compounds of the formula (I) and salts thereof (all the symbols are the same meanings as described in the specification). 
                 
 
     The compounds of the formula (I) possess inhibitory activity of N-type calcium channel, so they are useful as drug for prevention and/or treatment of cerebral infarct, transient ischemic attack, encephalomyelopathy after cardiac operation, spinal angiopathy, hypertension with stress, neurosis, epilepsy, asthma and pollakiuria etc. or agent for the treatment of pain.

CROSS-REFERENCE TO RELATED APPLICATION

This Application is a National Stage Application under 35 U.S.C. § 371of Application No. PCT/JP99/03776, filed Jul. 13, 1999.

THE FIELD OF THE ART

The present invention relates to amino acid derivatives of the formula(I), process for the preparation thereof and pharmaceutical composition,as active ingredients, them.

More particularly, it relates to amino acid derivatives of the formula(I)

(wherein all the symbols are the same meanings as hereinafterdescribed), non-toxic salts thereof and the hydrates thereof, processesfor the preparation thereof, and N-type calcium channel blockercomprising them as active ingredients.

BACKGROUND OF THE RELATED ARTS

Calcium ion has been known as an intracellular messenger for signaltransduction, and it is suggested that various physiological events aretriggered by the elevation of intracellular calcium concentration.Calcium influx from extracellular fluid is one of the mechanisms for theelevation of intracellular calcium concentration. The gate of calciuminflux is the voltage-dependent calcium channels. The voltage-dependentcalcium channel is opened by the polarization of plasma membrane, andcalcium ion influxes from extracellular fluid into the cell selectivelythrough the channel according to the electrochemical gradient. Thevoltage-dependent calcium channels are classified into N-, L-, P-, Q-and T-type at present. It is known that L- and T-type calcium channelsare distributed in the various tissues ubiquitously, and especially,L-type calcium channel is enriched in the smooth muscle cells or thecardiac muscle cells. On the other hand, N- and P-type calcium channelsare mainly located in the nervous system and related to theneurotransmitter release. This neurotransmitter is stored in synapticvesicles of nerve terminals at resting state. When action potential bysignal transmission on nerve is conducted in pre-synaptic fiber andreaches to the nerve terminal, the voltage-dependent calcium channelsare activated and then, calcium ion influxes into the nerve terminals.By these mechanisms, synaptic vesicles are fused with pre-synapticmembrane, and neurotransmitters in the vesicles are released. Thereleased neurotransmitters are related to signal transmission in synapsedue to binding to their receptors in post-synaptic membrane. From theabove, an N-type calcium channel blocker is thought to be effective onvarious diseases induced by an excessive release of neurotransmitter.For example, it may be useful as agent for the prevention and/ortreatment of cerebral infarct (J. Cereb. Blood Flow Metab., Vol. 17,421-429, 1997), transient ischemic attack, encephalomyelopathy aftercardiac operation, spinal angiopathy, hypertension with stress(Science., 239, 57-61, 1988), neurosis, epilepsy, asthma and pollakiuriaetc. or agent for the treatment of pain (for example, acute pain,chronic pain, pain after operation, cancer pain, neuralgia, pain causedby infection etc.) (Pain, 60, 83-90, 1995).

The venoms isolated from the genus Conus, ω-conotoxin GVIA, MVIIA, arewell known as N-type calcium channel blockers.

But, these ω-conotoxins are peptide compounds, so it is expected thatthey have various problems (for example, they are not absorbed into theliving body easily). Therefore, there is a demand for arrangement ofthese blockers to non-peptide compounds namely to small-molecule. Thereare some reports relate to small-molecule as follows:

For example, it is described in the specification of Japanese PatentKokai Hei 8-217671 that glycine derivatives of the formula (A)R^(1A)CH(OCOR^(2A))CH₂CONHCH₂CO₂H  (A)(wherein R^(1A) and R^(2A) are, same or different, C1-19 straight orbranched alkyl or C2-19 straight or branched alkenyl) and salts thereofare N-type calcium channel blocker.

It is described in the specification of EP 805147 that the compounds ofthe formula (B)

(wherein R^(1B) is alkyl, R^(2B) is hydrogen, optionally substitutedalkyl, optionally substituted aryl or optionally substituted heteroaryl,R^(3B) is hydrogen, CN, X^(B) is bond or SO₂, R^(4B), R^(5B), R^(6B),R^(8B), R^(9B) and R^(10B) are each hydrogen or alkyl, A^(B) is CH₂ orY^(B)CO (in which Y^(B) is bond), R^(7B) is C α-substituent of aminoacid or ester thereof, R^(6B) and R^(7B) together form C3-5 alkylenechain optionally substituted by C1-4 alkyl or hydroxy or CH₂—Z^(B)—CH₂(in which Z^(B) is CO, S, SO, SO₂), R^(7B) and R^(8B) together form C3-5alkylene chain optionally substituted by C1-4 alkyl or hydroxy, B^(B) isCON(R^(21B)), mB is 0˜2, R^(11B) is hydrogen or alkyl, R^(12B) ishydrogen, alkyl, optionally substituted aryl or optionally substitutedheteroaryl, R^(13B) is alkyl, optionally substituted aryl or optionallysubstituted heteroaryl, R^(12B) and R^(13B) together form C3-8cycloalkyl), the salts thereof or the ester thereof are calcium channelmodulator (necessary part is extracted in the explanation of the group).

Also, it is described in the specification of Japanese Patent Kokai Sho61-200950 that the compound of the formula (C)

(wherein R^(C) and R^(1C) each independently, is lower alkyl, aryl-loweralkyl or phenyl optionally substituted by one or moreelectron-withdrawing or electron-donating group, R^(2C) and R^(3C) eachindependently, is hydrogen, lower alkyl, aryl-lower alkyl or phenyloptionally substituted with one or more electron-withdrawing orelectron-donating group, and nC is 1˜4) and pharmaceutically acceptablesalts thereof are anti-convulsant agent.

In addition, the present inventors (applicant(s)) have filed twointernational applications relating to an N-type calcium channelinhibitor (WO99/02146 and international application No. PCT/99/03409(filing date: Jun. 25, 1999)).

Further, as for an application relating to an N-type calcium channelinhibitor, WO98/54123 is listed.

Besides the above applications, WO 99/25686 (cyclic amine derivativespossessing inhibitory action on chemokine) is listed.

DISCLOSURE OF THE INVENTION

As the result of energetic investigations in order to find compoundspossessing inhibitory action on N-type calcium channel, the presentinventors have found that the purpose has been accomplished by thecompound of the formula (I).

The present invention relates to,(1) an amino acid derivative of the formula (I)

-   -   [wherein,    -   R¹ is    -   1) phenyl,    -   2) C3-8 cycloalkyl,    -   3) heterocyclic ring,    -   4) C1-4 alkyl substituted with phenyl, C3-8 cycloalkyl or        heterocyclic ring,    -   5) C1-4 alkoxy substituted with phenyl, C3-8 cycloalkyl or        heterocyclic ring, or    -   6) C2-4 alkenyl substituted with phenyl, C3-8 cycloalkyl or        heterocyclic ring, provided that all the said phenyl, C3-8        cycloalkyl and heterocyclic ring in R¹ is substituted with (a)        four C1-4 alkyl or (b) one substituent selected from the        following (i)-(xii) essentially, and the said ring may be        substituted with 1˜3 of substituent(s) selected from the group        consisting of (i)-(xxiii):        -   (i) oxo,        -   (ii) C5-8 alkyl,        -   (iii) —COO—R⁵ (in which, R⁵ is hydrogen, C5-8 alkyl, C2-8            alkenyl, or C1-4 alkyl substituted with 1˜3 of halogen or            C1-4 alkoxy),        -   (iv) —(C1-4 alkylene)—COOR⁶ (in which, R⁶ is hydrogen, C1-8            alkyl, C2-8 alkenyl or C1-4 alkyl substituted with 1˜3 of            halogen),        -   (v) —CO—R⁷ (in which, R⁷ is C5-8 alkyl, C2-4 alkenyl,            carbocyclic ring, heterocyclic ring or C1-8 alkyl            substituted with one substituent selected from the following            (1)-(8);            -   (1) carbocyclic ring,            -   (2) heterocyclic ring,            -   (3) hydroxy,            -   (4) C1-4 alkoxy,            -   (5) —OCO—(C1-4 alkyl),            -   (6) —O—(C1-4 alkylene)-O—(C1-4 alkyl),            -   (7) NR⁸R⁹ (in which, R⁸ and R⁹ each, independently, is                hydrogen or C1-4 alkyl),            -   (8) halogen),        -   (vi) —(C1-4 alkylene)-CO—R¹⁰ (in which, R¹⁰ is C1-8 alkyl,            C2-4 alkenyl, carbocyclic ring, heterocyclic ring or C1-8            alkyl substituted with one substituent selected from the            following (1)-(8);            -   (1) carbocyclic ring,            -   (2) heterocyclic ring,            -   (3) hydroxy,            -   (4) C1-4 alkoxy,            -   (5) —OCO—(C1-4 alkyl),            -   (6) —O—(C1-4 alkylene)-O—(C1-4 alkyl),            -   (7) NR¹¹R¹² (in which, R¹¹ and R¹² each, independently,                is hydrogen or C1-4 alkyl),            -   (8) halogen),        -   (vii) —CO—CO—R¹³,        -   (viii) —CO—(C1-4 alkylene)-CO—R¹⁴,        -   (ix) —SO₂—R¹⁵ (in which, R¹³, R¹⁴ and R¹⁵ each,            independently, is C1-8 alkyl, C2-4 alkenyl, carbocyclic            ring, heterocyclic ring, hydroxy, C1-4 alkoxy or C1-8 alkyl            substituted with one substituent selected from the following            (1)-(8);            -   (1) carbocyclic ring,            -   (2) heterocyclic ring,            -   (3) hydroxy,            -   (4) C1-4 alkoxy,            -   (5) —OCO—(C1-4 alkyl),            -   (6) —O—(C1-4 alkylene)-O—(C1-4 alkyl),            -   (7) NR¹⁶R¹⁷ (in which, R¹⁶ and R¹⁷ each, independently,                is hydrogen or C1-4 alkyl),            -   (8) halogen),        -   (x) —CONR¹⁸R¹⁹ (in which, R¹⁸ is hydrogen or C1-4 alkyl            which may be substituted with one phenyl, R¹⁹ is C1-8 alkyl            or C2-4 alkenyl),        -   (xi) C1-8 alkyl substituted with 1˜2 of substituent(s)            selected from the group consisting of the following (1)-(7);            -   (1) hydroxy,            -   (2) C1-4 alkoxy,            -   (3) —O—(C1-4 alkylene)-O—(C1-4 alkyl),            -   (4) tetrahydropyran-2-yloxy,            -   (5) —SR²⁰ (in which, R²⁰ is hydrogen or C1-4 alkyl),            -   (6) halogen,            -   (7) NR²¹R²² (in which, R²¹ and R²² each, independently,                is hydrogen or C1-4 alkyl),        -   (xii) hydroxy,        -   (xiii) C1-4 alkyl,        -   (xiv) C1-4 alkoxy,        -   (xv) phenyl,        -   (xvi) phenoxy,        -   (xvii) benzyloxy,        -   (xviii) —SR²³ (in which, R²³ is hydrogen or C1-4 alkyl),        -   (xix) C2-5 acyl,        -   (xx) halogen,        -   (xxi) C1-4 alkoxycarbonyl,        -   (xxii) nitro,        -   (xxiii) —NR²⁴R²⁵ (in which, R²⁴ and R²⁵ each, independently,            is hydrogen, C1-4 alkyl or C1-4 alkoxycarbonyl, or R²⁴ and            R²⁵ taken together with nitrogen atom to which is attached            represents 5˜7-membered saturated heterocyclic ring            necessary containing one nitrogen atom and optionally            further containing one nitrogen atom or one oxygen atom),    -   A is single bond, —CO— or —SO₂—,    -   R² is hydrogen or C1-4 alkyl which may be substituted with one        phenyl,    -   D is C1-4 alkylene or C2-4 alkenylene,    -   E is    -   1) —COO—,    -   2) —OCO—,    -   3) —CONR²⁶— (in which, R²⁶ is hydrogen or C1-4 alkyl),    -   4) —NR²⁷CO— (in which, R²⁷ is hydrogen or C1-4 alkyl),    -   5) —O—,    -   6) —S—,    -   7) —SO—,    -   8) —SO₂—,    -   9) —NR²⁸— (in which, R²⁸ is hydrogen or C1-4 alkyl),    -   10) —CO—,    -   11) —SO₂NR²⁹— (in which, R²⁹ is hydrogen or C1-4 alkyl) or    -   12) —NR³⁰SO₂— (in which, R³⁰ is hydrogen or C1-4 alkyl),    -   R³ is    -   1) carbocyclic ring,    -   2) heterocyclic ring or    -   3) C1-4 alkyl substituted with carbocyclic ring or heterocyclic        ring, in which, all the said carbocyclic ring and heterocyclic        ring in R³ may be substituted with 1˜3 of substituent(s)        selected from the group consisting of the following (i)-(xi):        -   (i) C1-4 alkyl,        -   (ii) C1-4 alkoxy,        -   (iii) phenyl,        -   (iv) phenoxy,        -   (v) benzyloxy,        -   (vi) —SR³¹ (in which, R³¹ is hydrogen or C1-4 alkyl),        -   (vii) C2-5 acyl,        -   (viii) halogen,        -   (ix) C1-4 alkoxycarbonyl,        -   (x) nitro,        -   (xi) —NR³²R³³ (in which, R³² and R³³ each, independently, is            hydrogen, C1-4 alkyl or C1-4 alkoxycarbonyl, or R³² and R³³            taken together with nitrogen atom to which is attached            represents 5˜7-membered saturated heterocyclic ring            necessary containing one nitrogen atom and optionally            further containing one nitrogen atom or one oxygen atom),    -   J is    -   1) —O—,    -   2) —NR³⁴— (in which, R³⁴ is hydrogen, C1-4 alkyl which may be        substituted with one phenyl, NR³⁵R³⁶ (in which, R³⁵ and R³⁶        each, independently, is hydrogen or C1-4 alkyl), hydroxy, C1-4        alkoxy, —(C1-4 alkylene)-OH, —(C1-4 alkylene)-O—(C1-4 alkyl) or        —(C1-4 alkylene)-O—(C2-5 acyl)),    -   3) —NR³⁷—NR³⁸— (in which, R³⁷ and R³⁸ each, independently, is        hydrogen or C1-4 alkyl which may be substituted with one        phenyl),    -   4) —NR³⁹—(C1-4 alkylene)-NR⁴⁰— (in which, R³⁹ and R⁴⁰ each,        independently, is hydrogen or C1-4 alkyl which may be        substituted with one phenyl),    -   5) —NR⁴¹—(C1-4 alkylene)-O— (in which, R⁴¹ is hydrogen or C1-4        alkyl which may be substituted with one phenyl) or    -   6) —NR⁴²—(C1-4 alkylene)-S— (in which, R⁴² is hydrogen or C1-4        alkyl which may be substituted with one phenyl),    -   R⁴ is R⁴⁻¹ or R⁴⁻²,    -   R⁴⁻¹ is    -   1) C1-8 alkyl,    -   2) carbocyclic ring,    -   3) heterocyclic ring or    -   4) C1-8 alkyl substituted with 1˜3 of substituent(s) selected        from the group consisting of the following (i)-(v);        -   (i) carbocyclic ring,        -   (ii) heterocyclic ring,        -   (iii) COOR⁴³ (in which, R⁴³ is hydrogen or C1-4 alkyl            substituted with one phenyl (in which, phenyl may be            substituted with C1-4 alkoxy)),        -   (iv) SR⁴⁴ (in which, R⁴⁴ is hydrogen or C1-4 alkyl),        -   (v) OR⁴⁵ (in which, R⁴⁵ is hydrogen or C1-4 alkyl), or when            J is —NR³⁴—, —NR³⁷—NR³⁸— or —NR³⁹—(C1-4 alkylene)-NR⁴⁰—,            each R⁴⁻¹ and R³⁴, R⁴⁻¹ and R³⁸, and R⁴⁻¹ and R⁴⁰ taken            together with nitrogen atom to which is attached may            represent heterocyclic ring,    -   in which all the said carbocyclic ring and heterocyclic ring in        R⁴⁻¹, and heterocyclic ring represented by each R⁴⁻¹ and R³⁴,        R⁴⁻¹ and R³⁸, and R⁴⁻¹ and R⁴⁰ taken together with nitrogen atom        to which is attached may be substituted with 1˜3 of        substituent(s) selected from the group consisting of the        following (i)-(x):        -   (i) C1-4 alkyl,        -   (ii) C1-4 alkoxy,        -   (iii) —SR⁴⁶ (in which, R⁴⁶ is hydrogen or C1-4 alkyl),        -   (iv) C2-5 acyl,        -   (v) halogen,        -   (vi) C1-4 alkoxycarbonyl,        -   (vii) nitro,        -   (viii) —NR⁴⁷R⁴⁸ (in which, R⁴⁷ and R⁴⁸ each, independently,            is hydrogen, C1-4 alkyl or C1-4 alkoxycarbonyl),        -   (ix) hydroxy,        -   (x) —(C1-4 alkylene)-O—(C1-4 alkyl),    -   R⁴² is —L—M,    -   —L— is    -   1) -carbocyclic ring-,    -   2) -heterocyclic ring- or    -   3) —(C1-4 alkylene)-(carbocyclic ring or heterocyclic ring)-,    -   or when J is —NR³⁴—, —NR³⁷—NR³⁸— or —NR³⁹—(C1-4 alkylene)-NR⁴⁰—,        each L and R³⁴, L and R³⁸, and L and R⁴⁰ taken together with        nitrogen atom to which is attached may represent-heterocyclic        ring-,    -   M is    -   1) carbocyclic ring,    -   2) heterocyclic ring    -   3) C1-4 alkyl substituted with 1˜2 of substituent(s) selected        from the group consisting of the following (i)-(ii);        -   (i) carbocyclic ring,        -   (ii) heterocyclic ring,    -   4) —O-(carbocyclic ring or heterocyclic ring),    -   5) —S-(carbocyclic ring or heterocyclic ring),    -   6) —NR⁴⁹-(carbocyclic ring or heterocyclic ring) (in which, R⁴⁹        is hydrogen or C1-4 alkyl which may be substituted with one        phenyl),    -   7) —O—(C1-4 alkylene)-(carbocyclic ring or heterocyclic ring),    -   8) —S—(C1-4 alkylene)-(carbocyclic ring or heterocyclic ring),    -   9) —NR⁵⁰—(C1-4 alkylene)-(carbocyclic ring or heterocyclic ring)        (in which, R⁵⁰ is hydrogen, C1-4 alkyl which may be substituted        with one phenyl or C2-5 acyl which may be substituted with 1˜3        of halogen) or    -   10) —CO-(carbocyclic ring or heterocyclic ring),    -   or the said carbocyclic ring and heterocyclic ring in L and M,        and heterocyclic ring represented by each L and R³⁴, L and R³⁴,        and L and R⁴⁰ taken together with nitrogen atom to which is        attached may be substituted with 1˜3 of substituent(s) selected        from the group consisting of the following (i)-(xiv);        -   (i) C1-4 alkyl,        -   (ii) C2-4 alkenyl,        -   (iii) hydroxy,        -   (iv) C1-4 alkoxy,        -   (v) —(C1-4 alkylene)-OH,        -   (vi) —(C1-4 alkylene)-O—(C1-4 alkyl),        -   (vii) halogen,        -   (viii) NR⁵¹R⁵² (in which, R⁵¹ and R⁵² each, independently,            is hydrogen, C1-4 alkyl or C1-4 alkoxycarbonyl, or R⁵¹ and            R⁵² taken together with nitrogen atom to which is attached            represents 5˜7-membered saturated heterocyclic ring            necessary containing one nitrogen atom and optionally            further containing one nitrogen atom or one oxygen atom),        -   (ix) SR⁵³ (in which, R⁵³ is hydrogen or C1-4 alkyl),        -   (x) nitro,        -   (xi) trifluoromethyl,        -   (xii) C1-4 alkoxycarbonyl,        -   (xiii) oxo,        -   (xiv) C2-5 acyl] or    -   a non-toxic salt thereof, or a hydrate thereof,    -   (2) process for preparation of an amino acid derivative of the        formula (I) or a non-toxic salt thereof, or a hydrate thereof        and    -   (3) a pharmaceutical composition (N-type calcium channel        inhibitor) comprising, as an active ingredient, an amino acid        derivative of the formula (I) or a non-toxic salt thereof, or a        hydrate thereof.

Unless otherwise specified, all isomers are included in the presentinvention. For example, alkyl, alkenyl, alkynyl and alkylene groupincludes straight or branched ones. In addition, isomers on double bond,ring, fused ring (E-, Z-, cis-, trans-isomer), isomers generated fromasymmetric carbon atom(s) (R-, S-, α-, β-isomer, enantiomer,diastereomer), optically active isomers (D-, L-, d-, I-isomer), polarcompounds generated by chromatographic separation (more polar compound,less polar compound), equilibrium compounds, mixtures thereof atvoluntary ratios and racemic mixtures are also included in the presentinvention.

In the formula (I), C1-4 alkyl means methyl, ethyl, propyl, butyl andisomers thereof.

In the formula (I), C5-8 alkyl means pentyl, hexyl, heptyl, octyl andisomers thereof.

In the formula (I), C1-8 alkyl means methyl, ethyl, propyl, butyl,pentyl, hexyl, heptyl, octyl and isomers thereof.

In the formula (I), C3-8 cycloalkyl means cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

In the formula (I), C1-4 alkylene means methylene, ethylene, propylene,butylene and isomers thereof.

In the formula (I), C1-4 alkoxy means methoxy, ethoxy, propoxy, butoxyand isomers thereof.

In the formula (I), C2-4 alkenyl means ethenyl, propenyl, butenyl andisomers thereof.

In the formula (I), C2-8 alkenyl means ethenyl, propenyl, butenyl,pentenyl, hexenyl, heptenyl, octenyl and isomers thereof.

In the formula (I), C2-4 alkenylene means ethenylene, propenylene,butenylene and isomers thereof.

In the formula (I), C2-5 acyl means acetyl, propionyl, butyryl, valeryland isomers thereof.

In the formula (I), C1-4 alkoxycarbonyl means methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl and isomers thereof.

In the formula (I), halogen means fluoride, chloride, bromide andiodide.

In the formula (I), carbocyclic ring means C3-10 mono-, bi-carbocyclicring and fused carbocyclic ring. For example, the said C3-10 mono-,bi-carbocyclic ring and fused carbocyclic ring includes cyclopropane,cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane,cyclononane, cyclodecane, cyclopentene, cyclohexene, cyclopentadiene,cyclohexadiene, benzene, pentalene, indene, naphthalene, azulene,dihydronaphthalene, tetrahydronaphthalene, perhydronaphthalene, indane(dihydroindene), perhydroindene, bicyclopentane, bicyclohexane,bicycloheptane (bicyclo[2.2.1]heptane), bicycloheptene(bicyclo[2.2.1]hept-2-ene), bicyclooctane, bicyclononane, bicyclodecane,adamanthane etc.

In the formula (I), 5˜7-membered saturated heterocyclic ring containingone nitrogen atom and further optionally containing one nitrogen atom orone sulfur atom represented by each R²⁴ and R²⁵, R³² and R³³, and R⁵¹and R⁵² taken together with nitrogen atom to which is attached means forexample, pyrrolidine, piperidine, piperazine, morpholine,perhydroazepine.

In the formula (I), heterocyclic ring represented by each R⁴⁻¹ and R³⁴,R⁴⁻¹ and R³⁸, R⁴⁻¹ and R⁴⁰, L and R³⁴, L and R³⁸, and L and R⁴⁰ takentogether with nitrogen atom to which is attached means 5˜15-memberedmono- or bi-heterocyclic ring essentially containing one nitrogen atomand further optionally containing one nitrogen atom, one oxygen atomand/or one sulfur atom which is unsaturated or saturated partially orfully. For example, the said 5˜15-membered mono- or bi-heterocyclic ringessentially containing one nitrogen atom and further optionallycontaining one nitrogen atom, one oxygen atom and/or one sulfur atomwhich is unsaturated or saturated partially or fully includes pyrroline,pyrrolidine, imidazoline, imidazolidine, pyrazoline, pyrazolidine,piperidine, piperazine, tetrahydropyrimidine, hexahydropyrimidine,tetrahydropyridazine, hexahydropyridazine, hexahydroazepine,tetrahydrooxazole, tetrahydroisooxazole, tetrahydrothiazole,tetrahydroisothiazole, morpholine, thiomorpholine, indoline,isoindoline, dihydroindazole, perhydroindazole, dihydroquinoline,tetrahydroquinoline, perhydroquinoline, dihydroisoquinoline,tetrahydroisoquinoline, perhydroisoquinoline, dihydrophthalazine,tetrahydrophthalazine, perhydrophthalazine, dihydronaphthylidine,tetrahydronaphthylidine, perhydronaphthylidine, dihydroquinoxaline,tetrahydroquinoxaline, perhydroquinoxaline, dihydroquinazoline,tetrahydroquinazoline, perhydroquinazoline, dihydrocinnoline,tetrahydrocinnoline, perhydrocinnoline, dihydrobenzooxazole,perhydrobenzooxazole, dihydrobenzothiazole, perhydrobenzothiazole,dihydrobenzoimidazole, perhydrobenzoimidazole, pyrrole, imidazole,pyrazole, indole, isoindole, indazole, benzoimidazole etc.

In the formula (I), heterocyclic ring other than the above means5˜15-membered mono- or bi-heterocyclic ring containing 1˜2 nitrogenatom(s), 1˜2 oxygen atom(s) and/or one sulfur atom which is unsaturatedor saturated partially or fully (abbreviated as heterocyclic ring (A)).For example, the said 5˜15-membered mono- or bi-heterocyclic ringcontaining 1˜2 nitrogen atom(s), 1˜2 oxygen atom(s) and/or one sulfuratom which is unsaturated or saturated partially or fully includespyrroline, pyrrolidine, imidazoline, imidazolidine, pyrazoline,pyrazolidine, piperidine, piperazine, tetrahydropyrimidine,hexahydropyrimidine, tetrahydropyridazine, hexahydropyridazine,hexahydroazepine, dihydrofuran, tetrahydrofuran, dihydropyran,tetrahydropyran, dihydrothiophene, tetrahydrothiophene, dihydrothiain(dihydrothiopyran), tetrahydrothiain (tetrahydrothiopyran),dihydrooxazole, tetrahydrooxazole, dihydroisooxazole,tetrahydroisooxazole, dihydrothiazole, tetrahydrothiazole(thiazolidine), dihydroisothiazole, tetraisothiazole, morpholine,thiomorpholine, indoline, isoindoline, dihydroindazole,perhydroindazole, dihydroquinoline, tetrahydroquinoline,perhydroquinoline, dihydroisoquinoline, tetrahydroisoquinoline,perhydroisoquinoline, dihydrophthalazine, tetrahydrophthalazine,perhydrophthalazine, dihydronaphthylidine, tetrahydronaphthylidine,perhydronaphthylidine, dihydroquinoxaline, tetrahydroquinoxaline,perhydroquinoxaline, dihydroquinazoline, tetrahydroquinazoline,perhydroquinazoline, dihydrocinnoline, tetrahydrocinnoline,perhydrocinnoline, dihydrobenzooxazole, perhydrobenzooxazole,dihydrobenzothiazole, perhydrobenzothiazole, dihydrobenzoimidazole,perhydrobenzoimidazole, dihydrobenzoxazine, dioxaindane, benzodioxane,quinuclidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine,pyrimidine, pyridazine, pyridazine, azepine, diazepine, furan, pyran,oxepine, oxazepine, thiophene, thiain (thiopyran), thiepine, oxazole,isooxazole, thiazole, isothiazole, oxadiazole, oxazine, oxadiazine,oxazepine, oxadiazepine, thiadiazole, thiazine, thiadiazine, thiazepine,thiadiazepine, indole, isoindole, benzofuran, isobenzofuran,benzothiophene, isobenzothiophene, indazole, quinoline, isoquinoline,phthalazine, naphthylidine, quinoxaline, quinazoline, cinnoline,benzooxazole, benzothiazole, benzoimidazole, oxatetrahydrofuran etc.

R¹ is preferably heterocyclic ring or C1-4 alkyl substituted withheterocyclic ring, and more preferably heterocyclic ring (provided thatall the said heterocyclic ring is substituted). Such a heterocyclic ringincludes the said heterocyclic ring (A), preferably, 5˜15-membered mono-or bi-heterocyclic ring containing 1˜2 nitrogen atom(s), 1˜2 oxygenatom(s) or one sulfur atom which is unsaturated or saturated partiallyor fully (for example, dihydrooxazole, tetrahydrooxazole,dihydroisooxazole, tetrahydroisooxazole, dihydrothiazole,tetrahydrothiazole (thiazolidine), dihydroisothiazole, tetraisothiazole,morpholine, thiomorpholine, dihydrobenzooxazole, perhydrobenzooxazole,dihydrobenzothiazole, perhydrobenzothiazole, dihydrobenzoxazine,oxazepine, oxazole, isooxazole, thiazole, isothiazole, oxadiazole,oxazine, oxadiazine, oxazepine, oxadiazepine, thiadiazole, thiazine,thiadiazine, thiazepine, thiadiazepine, benzooxazole, benzothiazoleetc.), more preferably 5˜7-membered mono-heterocyclic ring containingone nitrogen atom and one oxygen atom or one sulfur atom which isunsaturated or saturated partially or fully (for example,dihydrooxazole, tetrahydrooxazole, dihydroisooxazole,tetrahydroisooxazole, dihydrothiazole, tetrahydrothiazole(thiazolidine), dihydroisothiazole, tetraisothiazole, morpholine,thiomorpholine, oxazepine, oxazole, isooxazole, thiazole, isothiazole,oxazine, oxazepine, thiazine, thiazepine etc.), and most preferablytetrahydrothiazole (thiazolidine).

In addition, each ring of R¹ is essentially substituted with (b-1) onesubstituent selected from the following (i), (ii), (iii-a), (iv)-(xii)and further may be substituted with 1˜3 of substituent(s) selected fromthe group consisting of the following (i), (ii), (iii-a), (iv)-(xxiii):

-   -   (i) oxo,    -   (ii) C5-8 alkyl,    -   (iii-a) —COO—R^(5A) (in which, R^(5A) is hydrogen, C5-8 alkyl,        C2-8 alkenyl or C1-4 alkyl substituted with 1˜3 of halogen),    -   (iv) —(C1-4 alkylene)-COOR⁶ (in which, R⁶ is hydrogen, C1-8        alkyl, C2-8 alkenyl or C1-4 alkyl substituted with 1˜3 of        halogen),    -   (v) —CO—R⁷ (in which, R⁷ is C5-8 alkyl, C2-4 alkenyl,        carbocyclic ring, heterocyclic ring or C1-8 alkyl substituted        with one substituent selected from the following (1)-(8);        -   (1) carbocyclic ring,        -   (2) heterocyclic ring,        -   (3) hydroxy,        -   (4) C1-4 alkoxy,        -   (5) —OCO—(C1-4 alkyl),        -   (6) —O—(C1-4 alkylene)-O—(C1-4 alkyl),        -   (7) NR⁸R⁹ (in which, R⁸ and R⁹ each, independently, is            hydrogen or C1-4 alkyl),        -   (8) halogen,    -   (vi) —(C1-4 alkylene)-CO—R¹⁰ (in which, R¹⁰ is C1-8 alkyl, C2-4        alkenyl, carbocyclic ring, heterocyclic ring or C1-8 alkyl        substituted with one substituent selected from the following        (1)-(8);        -   (1) carbocyclic ring,        -   (2) heterocyclic ring,        -   (3) hydroxy,        -   (4) C1-4 alkoxy,        -   (5) —OCO—(C1-4 alkyl),        -   (6) —O—(C1-4 alkylene)-O—(C1-4 alkyl),        -   (7) NR¹¹R¹² (in which, R¹¹ and R¹² each, independently, is            hydrogen or C1-4 alkyl),        -   (8) halogen,    -   (vii) —CO—CO—R¹³,    -   (viii) —CO—(C1-4 alkylene)-CO—R¹⁴,    -   (ix) —SO₂—R¹⁵ (in which, R¹³, R¹⁴ and R¹⁵ each, independently,        is C1-8 alkyl, C2-4 alkenyl, carbocyclic ring, heterocyclic        ring, hydroxy, C1-4 alkoxy or C1-8 alkyl substituted with one        substituent selected from the following (1)-(8);        -   (1) carbocyclic ring,        -   (2) heterocyclic ring,        -   (3) hydroxy,        -   (4) C1-4 alkoxy,        -   (5) —OCO—(C1-4 alkyl),        -   (6) —O—(C1-4 alkylene)-O—(C1-4 alkyl),        -   (7) NR¹⁶R¹⁷ (in which, R¹⁶ and R¹⁷ each, independently, is            hydrogen or C1-4 alkyl),        -   (8) halogen,    -   (x) —CONR¹⁸R¹⁹ (in which, R¹⁸ is hydrogen or C1-4 alkyl which        may be substituted with one phenyl, R¹⁹ is C1-8 alkyl or C2-4        alkenyl),    -   (xi) C1-8 alkyl substituted with 1˜2 of substituent(s) selected        from the group consisting of the following (1)-(7);        -   (1) hydroxy,        -   (2) C1-4 alkoxy,        -   (3) —O—(C1-4 alkylene)-O—(C1-4 alkyl),        -   (4) tetrahydropyran-2-yloxy,        -   (5) —SR²⁰ (in which, R²⁰ is hydrogen or C1-4 alkyl),        -   (6) halogen,        -   (7) NR²¹R²² (in which, R²¹ and R²² each, independently, is            hydrogen or C1-4 alkyl),    -   (xii) hydroxy,    -   (xiii) C1-4 alkyl,    -   (xiv) C1-4 alkoxy,    -   (xv) phenyl,    -   (xvi) phenoxy,    -   (xvii) benzyloxy,    -   (xviii) —SR²³ (in which, R²³ is hydrogen or C1-4 alkyl),    -   (xix) C2-5 acyl,    -   (xx) halogen,    -   (xxi) C1-4 alkoxycarbonyl,    -   (xxii) nitro,    -   (xxiii) —NR²⁴R²⁵ (in which, R²⁴ and R²⁵ each, independently, is        hydrogen, C1-4 alkyl or C1-4 alkoxycarbonyl, or R²⁴ and R²⁵        taken together with nitrogen atom to which is attached        represents 5˜7-membered saturated heterocyclic ring necessary        containing one nitrogen atom and optionally further containing        one nitrogen atom or one oxygen atom)    -   is preferable (in the following explanation, for example,        substituent “(i)”, “(iii)” of each ring in R¹ means    -   (i) oxo,    -   (iii) —COO—R⁵ (in which, R⁵ is hydrogen, C5-8 alkyl, C2-8        alkenyl or C1-4 alkyl substituted with 1-3 of halogen or C1-4        alkoxy)).

Further, when R¹ is group containing thiazolidine and such a ring issubstituted with the substituent (i) oxo, then the said oxo ispreferably bonded to the sulfur atom in thiazolidine ring.

In addition, when R¹ is group containing thiazolidine, the substituentof such a ring is preferably the said substituent (ii), (iii),(iv)-(xxiii).

The above group containing thiazolidine means thiazolidine, C1-4 alkylsubstituted with thiazolidine, C1-4 alkoxy substituted with thiazolidineand C2-4 alkenyl substituted with thiazolidine.

A is preferably single bond or —CO—, and more preferably —CO—.

D is preferably every group, more preferably C1-4 alkylene, and mostpreferably methylene.

R² is preferably every group, more preferably hydrogen or methylsubstituted with one phenyl, and most preferably hydrogen.

E is preferably —COO—, —O—, —S—, —SO— or —SO₂—, more preferably —O— or—S—, and most preferably —S—.

R³ is preferably carbocyclic ring or C1-4 alkyl substituted withcarbocyclic ring (provided that all the said carbocyclic ring may besubstituted), more preferably C3-10 cycloalkyl such as cyclopropane,cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane,cyclononane, cyclodecane or C1-4 alkyl substituted with C3-10 cycloalkyl(provided that all the said cycloalkyl may be substituted), much morepreferably cyclopentyl, cyclohexyl, or methyl substituted withcyclopentyl or cyclohexyl, and most preferably methyl substituted withcyclohexyl.

J is preferably —NR³⁴— (in which, R³⁴ is the same meaning ashereinbefore defined) or —NR³⁹—(C1-4 alkylene)-NR⁴⁰—, and morepreferably —NR³⁴—.

In R⁴, R⁴⁻¹ is preferably carbocyclic ring, heterocyclic ring or C1-8alkyl substituted with carbocyclic ring or heterocyclic ring, and morepreferably C1-8 alkyl substituted with carbocyclic ring, and mostpreferably C1-4 alkyl substituted with benzene (all the ring may besubstituted).

In R⁴, (—L—M) represented by R⁴⁻² is preferably the following group.

That is to say, L is preferably every group, and more preferablyheterocyclic ring (such a ring may be substituted). Such a heterocyclicring includes the said heterocyclicn ring (A), and preferably5˜15-membered mono- or bi-heterocyclicn ring containing 1˜2 nitrogenatom(s) which is unsaturated or saturated partially or fully (forexample, pyrroline, pyrrolidine, imidazoline, imidazolidine, pyrazoline,pyrazolidine, piperidine, piperazine, tetrahydropyrimidine,hexahydropyrimidine, tetrahydropyridazine, hexahydropyridazine,hexahydroazepine, indoline, isoindoline, dihydroindazole,perhydroindazole, dihydroquinoline, tetrahydroquinoline,perhydroquinoline, dihydroisoquinoline, tetrahydroisoquinoline,perhydroisoquinoline, dihydrophthalazine, tetrahydrophthalazine,perhydrophthalazine, dihydronaphthylidine, tetrahydronaphthylidine,perhydronaphthylidine, dihydroquinoxaline, tetrahydroquinoxaline,perhydroquinoxaline, dihydroquinazoline, tetrahydroquinazoline,perhydroquinazoline, dihydrocinnoline, tetrahydrocinnoline,perhydrocinnoline, dihydrobenzoimidazole, perhydrobenzoimidazole,quinuclidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine,pyrimidine, pyridazine, pyridazine, azepine, diazepine, indole,isoindole, indazole, quinoline, isoquinoline, phthalazine,naphthylidine, quinoxaline, quinazoline, cinnoline, benzoimidazoleetc.), more preferably 5˜7-membered mono-heterocyclicn ring containing1˜2 nitrogen atom(s) which is unsaturated or saturated partially orfully (for example, pyrroline, pyrrolidine, imidazoline, imidazolidine,pyrazoline, pyrazolidine, piperidine, piperazine, tetrahydropyrimidine,hexahydropyrimidine, tetrahydropyridazine, hexahydropyridazine,hexahydroazepine, pyrrole, imidazole, pyrazole, pyridine, pyrazine,pyrimidine, pyridazine, pyridazine, azepine, diazepine etc.), and mostpreferably piperidine.

Further, M is preferably every group, more preferably C1-4 alkylsubstituted with 1˜2 of substituent(s) selected from the groupconsisting of carbocyclic ring and heterocyclic ring, much morepreferably C1-4 alkyl substituted with 1˜2 of substituent(s) selectedfrom the group consisting of phenyl and C3-10 cycloalkyl, and mostpreferably methyl substituted with one phenyl (all the ring may besubstituted).

In R⁴, group represented by each R⁴⁻¹ and R⁴⁻² is preferable, and grouprepresented by R⁴⁻² is more preferable.

[Salts]

All the non-toxic salts are also included in the present invention. Forexample, the compounds of the formula (I) of the present invention maybe converted into the corresponding salts by known methods. Non-toxicand water-soluble salts are preferable. Suitable salts, for example, arefollows: salts of alkaline metals (potassium, sodium etc.), salts ofalkaline earth metals (calcium, magnesium etc.), ammonium salts, saltsof pharmaceutically acceptable organic amines (tetramethylammonium,triethylamine, methylamine, dimethylamine, cyclopentylamine,dicyclohexylamine, benzylamine, phenethylamine, piperidine,monoethanolamine, diethanolamine, tris(hydroxymethyl)amine, lysine,arginine, N-methyl-D-glucamine etc.).

The compounds of the formula (I) of the present invention may beconverted into the corresponding acid additional salts by methods knownper se. Non-toxic and water-soluble acid addition salts are preferable.Suitable acid addition salts, for example, are salts of inorganic acids,e.g., hydrochloride, hydrobromide, sulphate, phosphate, nitrate etc., orsalts of organic acids, e.g., acetate, trifluoroacetate, lactate,tartarate, oxalate, fumarate, maleate, citrate, benzoate,methanesulphonate, ethanesulphonate, benzenesulphonate,toluenesulphonate, isethioate, glucuronate, gluconate etc.

The compounds of the formula (I) of the present invention or saltsthereof may be converted into hydrate thereof by methods known per se.

In the compounds of the formula (I), the compounds of the formula (Ia)

(wherein all the symbols are the same meanings as defined hereinbefore),the compounds of the formula (Ib)

(wherein all the symbols are the same meanings as defined hereinbefore),the compounds of the formula (Ic)

(wherein all the symbols are the same meanings as defined hereinbefore),the compounds of the formula (Id)

(wherein all the symbols are the same meanings as defined hereinbefore),the compounds of the formula (Ie)

(wherein all the symbols are the same meanings as defined hereinbefore),the compounds of the formula (If)

(wherein all the symbols are the same meanings as defined hereinbefore),the compounds of the formula (Ig)

(wherein all the symbols are the same meanings as defined hereinbefore),and the compounds of the formula (Ih)

(wherein all the symbols are the same meanings as defined hereinbefore),non-toxic salts thereof, or hydrates thereof are preferable. Thecompounds of the formula (Ia) or (Ib) (wherein all the symbols are thesame meanings as defined hereinbefore), non-toxic salts thereof, orhydrates thereof are preferable.

The concrete compounds are ones shown in the following Tables 1-40,non-toxic salts thereof and the hydrates thereof and ones described inExample s. Also, the following concrete compounds include the isomersgenerated by asymmetric carbon atom(s), i.e., R, S and RS form. In thefollowing each Table, Me is methyl and R⁵⁴ is the same meaning of thesubstituent (i)-(xxiii) of the said heterocyclic ring.

TABLE 1 (Ia-1)

No. R⁵⁴  1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

TABLE 2 (Ia-2)

No. R⁵⁴  1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

TABLE 3 (Ia-3)

No. R⁵⁴  1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

TABLE 4 (Ia-4)

No. R⁵⁴  1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

TABLE 5 (Ia-5)

No. R⁵⁴  1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

TABLE 6 (Ib-1)

No. R⁵⁴  1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

TABLE 7 (Ib-2)

No. R⁵⁴  1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

TABLE 8 (Ib-3)

No. R⁵⁴  1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

TABLE 9 (Ib-4)

No. R⁵⁴  1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

TABLE 10 (Ib-5)

No. R⁵⁴  1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

TABLE 11 (Ic-1)

No. R⁵⁴  1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

TABLE 12 (Ic-2)

No. R⁵⁴  1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

TABLE 13 (Ic-3)

No. R⁵⁴  1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

TABLE 14 (Ic-4)

No. R⁵⁴  1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

TABLE 15 (Ic-5)

No. R⁵⁴  1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

TABLE 16 (Id-1)

No. R⁵⁴  1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

TABLE 17 (Id-2)

No. R⁵⁴  1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

TABLE 17 (Id-3)

No. R⁵⁴  1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

TABLE 19 (Id-4)

No. R⁵⁴  1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

TABLE 20 (Id-5)

No. R⁵⁴  1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

TABLE 21 (Ie-1)

No. R⁵⁴  1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

TABLE 22 (Ie-2)

No. R⁵⁴  1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

TABLE 23 (Ie-3)

No. R⁵⁴  1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

TABLE 24 (Ie-4)

No. R⁵⁴  1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

TABLE 25 (Ie-5)

No. R⁵⁴  1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

TABLE 26 (If-1)

No. R⁵⁴  1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

TABLE 27 (If-2)

No. R⁵⁴  1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

TABLE 28 (If-3)

No. R⁵⁴  1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

TABLE 29 (If-4)

No. R⁵⁴  1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

TABLE 30 (If-5)

No. R⁵⁴  1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

TABLE 31 (Ig-1)

No. R⁵⁴  1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

TABLE 32 (Ig-2)

No. R⁵⁴  1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

TABLE 33 (Ig-3)

No. R⁵⁴  1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

TABLE 34 (Ig-4)

No. R⁵⁴  1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

TABLE 35 (Ig-5)

No. R⁵⁴  1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

TABLE 36 (Ih-1)

No. R⁵⁴  1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

TABLE 37 (Ih-2)

No. R⁵⁴  1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

TABLE 38 (Ih-3)

No. R⁵⁴  1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

TABLE 39 (Ih-4)

No. R⁵⁴  1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

TABLE 40 (Ih-5)

No. R⁵⁴  1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

[Process for preparation of the compounds of the present invention]

(a) The compounds of the formula (I), wherein E is —COO—, —OCO—,—CONR²⁶—, —NR²⁷CO—, —O—, —S— or —CO—, i.e., the compounds of the presentinvention of the formula (I-A)

(wherein, R¹⁻¹ is the same meaning as hereinbefore described for R¹,provided that hydroxy, —COOH or amino group in R¹⁻¹ is protected withprotecting group, if necessary, R³⁻¹ is the same meaning as hereinbeforedescribed for R³, provided that amino group in R³⁻¹ is protected withprotecting group, if necessary, R⁴⁻³ is the same meaning as hereinbeforedescribed for R⁴, provided that —COOH, hydroxy or amino group in R⁴⁻³ isprotected with protecting group, if necessary, J¹ is the same meaning ashereinbefore described for J, provided that amino or hydroxy group in J¹is protected with protecting group, if necessary, E¹ is —COO—, —OCO—,—CONR²⁶—, —NR²⁷CO—, —O—, —S— or —CO— and the other symbols are the samemeanings as defined hereinbefore) may be prepared by amidation oresterification of the compounds of the formula (II)

(wherein all the symbols are the same meanings as defined hereinbefore)with the compounds of the formula (III)J²—R⁴⁻³  (III)(wherein, J² is —OH, —NHR³⁴⁻¹ (in which, R³²⁻¹ is the same meaning ashereinbefore described for R³², provided that amino or hydroxy group inR³⁴⁻¹ is protected with protecting group if necessary), —NR³⁸—NHR³⁷,—NR⁴⁰—(C1-4 alkylene)-NHR³⁹, —O—(C1-4 alkylene)-NHR⁴¹, —S—(C1-4alkylene)-NHR⁴² or heterocyclic ring possessing NH (this heterocyclicring is the same meaning as hereinbefore described for the heterocyclicring represented by each R⁴⁻¹ and R³⁴, R⁴⁻¹ and R³⁸, R⁴⁻¹ and R⁴⁰, L andR³⁴, L and R³⁸, and L and R⁴⁰ taken together with nitrogen atom to whichthey are attached) (in which all the symbols are the same meanings asdefined hereinbefore) and R⁴⁻³ is the same meaning as hereinbeforedescribed) or by amidation or esterification of the compounds of theformula (IV)

(wherein, E² is —COOH, —NHR²⁷ (in which R²⁷ is the same meaning asdefined hereinbefore) or —OH and the other symbols are the same meaningsas defined hereinbefore) with the compounds of the formula (V)E³—R³⁻¹  (v)(wherein, E³ is —OH, —NHR²⁶ (in which R²⁶ is the same meaning as definedhereinbefore) or —COOH and the other symbols are the same meanings asdefined hereinbefore).

The amidation is well known. For example, it may be carried out

-   (1) by the method with using acid halide,-   (2) by the method with using mixed acid anhydride,-   (3) by the method with using conducing agent etc.

Concrete description of these methods are as follows:

(1) Method with using acid halide may be carried out, for example;carboxylic acid is reacted with an acid halide (oxalyl chloride, thionylchloride or isobutyl chloroformate etc.) in an organic solvent(chloroform, methylene chloride, diethyl ether, tetrahydrofuran or ethylacetate etc.) or without solvents at from −20° C. to a refluxingtemperature to give an acid halide. The obtained acid halide and anamine are reacted in an organic solvent (chloroform, methylene chloride,diethyl ether, tetrahydrofuran etc.) in the presence of tertiary amine(pyridine, triethylamine, dimethylaniline, dimethylaminopyridine orN-methylmorpholine etc.) at 0˜40° C.

(2) Method with using mixed acid anhydride may be carried out, forexample; carboxylic acid is reacted with an acid halide (pivaloylchloride, tosyl chloride, mesyl chloride, ethyl chloroformate, isobutylchloroformate etc.) in an organic solvent (chloroform, methylenechloride, diethyl ether, tetrahydrofuran etc.) or without solvents, inthe presence of tertiary amine (pyridine, triethylamine dimethylaniline,dimethylaminopyridine or N-methylmorpholine etc.) at −20˜40° C. to givemixed acid anhydride. The obtained mixed acid anhydride andcorresponding amine are reacted in an organic solvent (chloroform,methylene chloride, diethyl ether, tetrahydrofuran etc.) at 0˜40° C.

(3) Method with using condensing agent (1,3-dicyclohexylcarbodiimido(DCC), 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimido (EDC),2-chloro-1-methylpyridinium iodide, 1,1′-carbonydiimidazole (CDI) etc.)may be carried out, for example; a carboxylic acid and an amine arereacted in an organic solvent (chloroform, methylene chloride,dimethylformamide, diethyl ether or tetrahydrofuran etc.) or withoutsolvents in the presence or absence of tertiary amine (pyridine,triethylamine, dimethylaniline or dimethylaminopyridine etc.) using withcondensing agent and using or without 1-hydroxybenzotriazole (HoBt) at0˜40° C.

Preferably, the above reactions (1), (2) and (3) described above arecarried out under an atmosphere of an inert gas (argon, nitrogen etc.)on anhydrous condition.

The esterification is well known. For example, it may be carried out

-   (1) by the method with using acid halide,-   (2) by the method with using mixed acid anhydride,-   (3) by the method with using conducing agent etc.

Concrete description of these methods are as follows:

(1) Method with using acid halide may be carried out, for example;carboxylic acid is reacted with an acid halide (oxalyl chloride, thionylchloride or isobutyl chloroformate etc.) in an organic solvent(chloroform, methylene chloride, diethyl ether, tetrahydrofuran or ethylacetate etc.) or without solvents at from −20° C. to a refluxingtemperature to give an acid halide. The obtained acid halide and analcohol are reacted in an organic solvent (chloroform, methylenechloride, diethyl ether, tetrahydrofuran etc.) in the presence oftertiary amine (pyridine, triethylamine, dimethylaniline,dimethylaminopyridine or N-methylmorpholine etc.) at 0˜40° C.

(2) Method with using mixed acid anhydride may be carried out, forexample; carboxylic acid is reacted with an acid halide (pivaloylchloride, tosyl chloride, mesyl chloride, ethyl chloroformate, isobutylchloroformate etc.) in an organic solvent (chloroform, methylenechloride, diethyl ether, tetrahydrofuran etc.) or without solvents, inthe presence of tertiary amine (pyridine, triethylamine,dimethylaniline, dimethylaminopyridine or N-methylmorpholine etc.) at−20˜40° C. to give mixed acid anhydride. The obtained mixed acidanhydride and corresponding alcohol are reacted in an organic solvent(chloroform, methylene chloride, diethyl ether, tetrahydrofuran etc.) at0˜40° C.

(3) Method with using condensing agent (1,3-dicyclohexylcarbodiimido(DCC), 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimido (EDC),2-chloro-1-methylpyridinium iodide, 1,1′-carbonydiimidazole (CDI) etc.)may be carried out, for example; a carboxylic acid and an alcohol arereacted in an organic solvent (chloroform, methylene chloride,dimethylformamide, diethyl ether or tetrahydrofuran etc.) or withoutsolvents in the presence or absence of tertiary amine (pyridine,triethylamine, dimethylaniline or dimethylaminopyridine etc.) using withcondensing agent and using or without 1-hydroxybenzotriazole (HoBt) at0˜40° C.

Preferably, the above reactions (1), (2) and (3) described above arecarried out under an atmosphere of an inert gas (argon, nitrogen etc.)on anhydrous condition.

The compounds of the formula (I-A), wherein E¹ is —S— i.e., thecompounds of the formula (I-A-1)

(wherein all the symbols are the same meanings as defined hereinbefore)may be prepared by reacting the compounds of the formula (VI)

(wherein all the symbols are the same meanings as defined hereinbefore)with the compounds of the formula (VII)X—R³⁻¹  (VII)(wherein, X is halogen and the other symbols are the same meanings asdefined hereinbefore).

The reaction of the compounds of the formula (VI) and the compounds ofthe formula (VII) may be carried out by known methods. For example, itmay be carried out in an organic solvent (dimethylformamide, acetoneetc.) in the presence of base (potassium carbonate etc.) at 0˜40° C.

(b) The compounds of the formula (I), wherein E is —SO—, —SO₂—. i.e.,the compounds of the formula (I-B)

(wherein, E⁴ is —SO— or —SO₂— and the other symbols are the samemeanings as defined hereinbefore)may be prepared by oxidation of the said compounds of the formula (I-A)wherein E¹ is —S—.

The oxidation is known per se. In case of oxidation of sulfide intosulfoxide, it may be carried out, for example, in an organic solvent(methylene chloride, chloroform, benzene, hexane, t-butyl alcohol etc.)in the presence of one equivalent of oxidizing agent (hydrogen peroxide,sodium periodate, acyl nitrite, sodium perborate, peracid (e.g.,m-chloroperbenzoic acid, peracetic acid etc.) etc.) for a few minutes at−78˜0° C.

In case of oxidation of sulfide into sulfon, it may be carried out, forexample, in an organic solvent (methylene chloride, chloroform, benzene,hexane, t-butyl alcohol etc.) in the presence of an excessive amount ofoxidizing agent (hydrogen peroxide, sodium periodate, potassiumpermanganate, sodium perbromate, potassium peroxymonosulfate, peracid(e.g., m-chloroperbenzoic acid, peracetic acid etc.) etc.) for a fewhours at −78˜40° C.

(c) The compounds of the formula (I), wherein E is —NR²⁸—, i.e., thecompounds of the formula (I-C)

(wherein all the symbols are the same meanings as defined hereinbefore)may be prepared by reacting the compounds of the formula (VIII)

(wherein all the symbols are the same meanings as defined hereinbefore)with the compounds of the formula (IX)NHR²⁸R³⁻¹  (IX)((wherein all the symbols are the same meanings as definedhereinbefore).

The reaction of the compounds of the formula (VIII) and the compounds ofthe formula (IX) may be carried out by known methods, for example, byreacting the compounds of the formula (VIII) and the compounds of theformula (IX) in an organic solvent (methanol, ethanol etc.) usingreductant (sodium cyanoborohydride, sodium borohydride, etc.) or usingpH adjustifying agent (acetic acid etc.) if necessary, at 0˜40° C.

(d) The compounds of the formula (I), wherein E is —SO₂NR²⁹—, i.e., thecompounds of the formula (I-D)

(wherein all the symbols are the same meanings as defined hereinbefore)may be prepared by reacting the compounds of the formula (X)

(wherein all the symbols are the same meanings as defined hereinbefore)with the compounds of the formula (XI)NHR²⁹—R³⁻¹  (XI)(wherein all the symbols are the same meanings as defined hereinbefore).

The reaction of the compounds of the formula (X) and the compounds ofthe formula (XI) may be carried out by known methods, for example, byreacting the compounds of the formula (X) with base (triphenylphosphineetc.) and acid halide (oxazolyl chloride, thionyl chloride etc.) in anorganic solvent (chloroform, methylene chloride, diethyl ether,tetrahydrofran etc.), at from −20° C. to refluxing temperature, and thenby reacting thus obtained compounds and the compounds of the formula(XI) in the presence of tertiary amine (pyridine, triethylamine,dimethylaniline, dimethylaminopyridine etc.) in an organic solvent(chloroform, methylene chloride, diethyl ether, tetrahydrofran etc.) at0˜40° C.

(e) The compounds of the formula (I), wherein E is —NR³⁰SO₂—, i.e., thecompounds of the formula (I-E)

(wherein all the symbols are the same meanings as defined hereinbefore)may be prepared by reacting the compounds of the formula (XII)

(wherein all the symbols are the same meanings as defined hereinbefore)with the compounds of the formula (XIII)X—SO₂—R³⁻¹  (XIII)(wherein, X is halogen and the other symbols are the same meanings asdefined hereinbefore).

The reaction of the compounds of the formula (XII) and the compounds ofthe formula (XIII) may be carried out, for example, by reacting thecompounds of the formula (XII) and the compounds of the formula (XIII)in an organic solvent (chloroform, methylene chloride, diethyl ether,tetrahydrofran etc.) in the presence of tertiary amine (pyridine,triethylamine, dimethylaniline, dimethylaminopyridine etc.) at 0˜40° C.

(f) The compounds of the formula (I), wherein A is —CO— or —SO₂—, i.e.,the compounds of the formula (I-F)

(wherein, A¹ is —CO— or —SO₂— and the other symbols are the samemeanings as defined hereinbefore)may be prepared by amidation or sulfonamidation of the compounds of theformula (XIV)

(wherein all the symbols are the same meanings as defined hereinbefore)with the compounds of the formula (XV) R¹⁻¹—A²  (XV)(wherein, A² is —COOH or —SO₃H and the other symbols are the samemeanings as defined hereinbefore).

The sulfonamidation is well known. For example, it may be carried out byreacting sulfonic acid and an acid halide (oxalyl chloride, thionylchloride, phosphorus pentachloride or phosphorus trichloride etc.) in anorganic solvent (chloroform, methylene chloride, diethyl ether ortetrahydrofuran etc.) or without solvents at from −20° C. to a refluxingtemperature to give a sulfonyl halide, and then by reacting the obtainedsulfonyl halide and an amine in an organic solvent (chloroform,methylene chloride, diethyl ether, tetrahydrofuran etc.) in the presenceof tertiary amine (pyridine, triethylamine, dimethylaniline ordimethylaminopyridine etc.) at 0˜40° C.

The amidation may be carried out by the same method describedhereinbefore.

(g) The compounds of the formula (I), wherein A is single bond and R¹ isC1-4 alkyl substituted with phenyl, C3-8 cycloalkyl or heterocyclicring, i.e., the compounds of the formula (I-G)

(R¹⁻² is C1-4 alkyl substituted with phenyl, C3-8 cycloalkyl orheterocyclic ring (with the proviso that when amino, hydroxy or —COOHgroup exists as a substituent of each ring, such amino, hydroxy or —COOHgroup is protected with protecting group, if necessary) and the othersymbols are the same meanings as defined hereinbefore)may be prepared by reacting the compounds of the formula (XIV)

(wherein all the symbols are the same meanings as defined hereinbefore)with the compounds of the formula (XVI)R¹⁻³—CHO  (XVI)(wherein, R¹⁻³ is phenyl, C3-8 cycloalkyl, heterocyclic ring or C1-3alkyl substituted with phenyl, C3-8 cycloalkyl or heterocyclic ring(with the proviso that when amino, hydroxy or —COOH group exists as asubstituent of each ring, such amino, hydroxy or —COOH group isprotected with protecting group, if necessary)).

This reaction may be carried out by the same procedure as described inthe reaction of the compounds of the formula (VIII) and the compounds ofthe formula (IX).

(h) The compounds of the formula (I) in which, R¹ is heterocyclic ring,C1-4 alkyl substituted with heterocyclic ring, and substituent of thesaid heterocyclic ring is (iii) —COOR⁵, (v) —CO—R⁷, (vii) —CO—CO—R¹³,(viii) —CO—(C1-4 alkylene)-CO—R¹⁴, (ix) —SO₂—R¹⁵, (x) —CONR¹⁸R¹⁹, (xix)C2-5 acyl or (xxi) C1-4 alkoxycarbonyl, i.e., compounds of the formula(I-H)

(wherein, R⁵⁵ is single bond or C1-4 alkylene, R⁵⁶ is the same meaningas the said substituent (iii), (v), (vii), (viii), (ix), (x), (xix) or(xxi) of heterocyclic ring, provided that amino, hydroxy or —COOH groupexists in the said substituent, such a group is protected withprotecting group if necessary, R⁵⁷ is the same meaning as the saidsubstituent (i)-(xxiii) of heterocyclic ring, provided that amino,hydroxy or —COOH group exists in the said substituent, such a group isprotected with protecting group if necessary, n is 0-3 and

is the same meaning as the said heterocyclic ring in R¹, provided thatsuch a ring contains at least one nitrogen atom)may be prepared by amidation or sulfonamidation of compounds of theformula (XVII)

(wherein, all the symbols are the same meaning as defined hereinbefore)with compounds of the formula (XVIII)R⁵⁶—OH  (XVIII)(wherein, R⁵⁶ is the same meaning as defined hereinbefore).

The amidation or sulfonamidation may be carried out by the same methoddescribed hereinbefore.

(i) The compounds of the formula (I) in which, R¹ is heterocyclic ringor C1-4 alkyl substituted with heterocyclic ring, and substituent of thesaid heterocyclic ring is (ii) C5-8 alkyl, (iv) —(C1-4 alkylene)-COOR⁶,(vi) —(C1-4 alkylene)-CO—R¹⁰, (xi) C1-8 alkyl substituted with 1˜2 ofsubstituent(s) selected from the group consisting of (1)-(7) or (xiii)C1-4 alkyl, i.e., compounds of the formula (I-I)

(wherein, R⁵⁸ is the same meaning as the said substituent (ii), (iv),(vi), (xi) or (xiii) of heterocyclic ring, provided that amino, hydroxyor —COOH group exists in the said substituent, such a group is protectedwith protecting group if necessary and all the symbols are the samemeanings as defined hereinbefore)may be prepared by reacting compounds of the formula (XVII) andcompounds of the formula (XVIV)R⁵⁹—CHO  (XVIV)(wherein, R⁵⁹ is C4-7 alkyl, —COOR⁶, —(C1-3 alkylene)-COOR⁶, —CO—R¹⁰,—(C1-3 alkylene)-CO—R¹⁰, (xi) C1-7 alkyl substituted with 1˜2 ofsubstituent(s) selected from the group consisting of (1)-(7) or C1-3alkyl (in which all the symbols are the same meanings as definedhereinbefore, provided that amino, hydroxy or —COOH group exists in thesaid substituent, such a group is protected with protecting group ifnecessary).

This reaction may be carried out by the same method as reaction of thesaid compounds of the formula (VIII) with compounds of the formula (IX).

(j) The compounds of the formula (I) in which, R¹ is heterocyclic ringor C1-4 alkyl substituted with heterocyclic ring, and substituent of thesaid heterocyclic ring is (x) —CONHR¹⁹, i.e., compounds of the formula(I-J)

(wherein, all the symbols are the same meaning as defined hereinbefore)may be prepared by reacting the said compounds of the formula (XVII) andcompounds of the formula (XVV)R¹⁹—N═C═O  (XVV)(wherein, R¹⁹ is the same meaning as defined hereinbefore).

This reaction may be carried out by known methods. For example, it maybe carried out by reacting compounds of the formula (XVII) and compoundsof the formula (XVV) in organic solvent (chloroform, methylene chloride,diethyl ether, tetrahydrofuran etc.), in the presence of base(triethylamine, pyridine, dimethylaniline, dimethylaminopyridine,N-methylmorpholine etc.), at from 0° C. to refluxing temperature.

(k) Among the compounds of the formula (I), the compounds of the formula(I-K)

(wherein, R¹⁻⁴, R³⁻², R⁴⁻⁴ and J³ are the same meanings as hereinbeforedescribed for R¹, R³, R⁴ and J respectively, provided that at least oneof them is a group containing —COOH, hydroxy or amino and the othersymbols are the same meanings as defined hereinbefore)may be prepared by removal of protecting group according to alkalinehydrolysis, by removal of protecting group in an acidic condition and/orby hydrogenolysis of the compounds of the said formulae (I-A), (I-A-1),(I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (I-I) or (I-J).

The removal of a protecting group according to alkaline hydrolysis iswell known. For example, it may be carried out in an organic solvent(methanol, tetrahydrofuran, dioxane etc.), using hydroxide of analkaline metal (sodium hydroxide, potassium hydroxide, lithium hydroxideetc.), hydroxide of an alkaline earth metal (calcium hydroxide etc.) orcarbonate (sodium carbonate, potassium carbonate etc.) or an aqueoussolution thereof or a mixture thereof at 0˜40° C.

The removal of a protecting group in an acidic condition is well known.For example, it may be carried out in an organic solvent (methylenechloride, chloroform, dioxane, ethyl acetate, anisole etc.) or withoutsolvent, in the presence of organic acid (trifluoroacetic acid,methanesulfonic acid, trimethylsilyliodide etc.) or inorganic acid(hydrochloric acid etc.) or a mixture thereof (bromohydroacetic acidetc.) at 0˜90° C.

The hydrogenolysis is well known. For example, it may be carried out inan organic solvent (tetrahydrofran, dioxane, diethyl ether, ethylacetate, methanol, ethanol etc.), in the presence of catalyst tohydrogenate (e.g., Pd—C, palladium, palladium hydroxide, palladiumacetate, palladium black, platinum black, Ni, Raney nickel etc.), at anordinary or increased pressure under an atmosphere of hydrogen gas at0˜80° C.

As well known to the person in the art, a protecting group of carboxy orhydroxy includes, for example, t-butyl, benzyl etc. In addition, such agroup includes the other protecting group which is removable selectivelyand easily, for example, one described in T. W. Greene, ProtectiveGroups in Organic Synthesis, Wiley, New York, 1991. A protecting groupof amino includes, for example, benzyloxycarbonyl, t-butoxycarbonyl. Inaddition, such a group includes the other protecting group which isremovable selectively and easily. Further, the aimed compounds of thepresent invention may be prepared easily by choice of these protectinggroup.

The compounds of the formula (I) may be prepared by the methodsdescribed in Examples or by known methods.

The compounds of the formulae (II), (III), (IV), (V), (VI), (VII),(VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII),(XVIII), (XVIV), (XVV) may be known per se or may be prepared by knownmethods or the methods described in Examples. But, the above compoundsmay be prepared by the other methods.

For example, the compounds of the formula (X) may be prepared by themethod described in Liebigs Ann. Chem, 776-783, 1979.

For example, the compounds of the formula (XII) may be prepared by themethod described in J. Org. Chem., Vol. 44, No. 10, 1979.

For example, the compounds of the formula (XIV), wherein E is —O—, —S—,—SO—, —SO₂—, i.e., the compounds of the formula (XIV′) and the compoundsof the formula (XVII), wherein E is —O—, —S—, —SO—, —SO₂—, i.e., thecompounds of the formula (XVII′) may be prepared by the method shown inthe following Reaction Schemes 1 and 2.

In each Reaction Scheme, E⁵ is —O—, —S—, —SO— or SO₂—, Boc ist-butoxycarbonyl, (Boc) ₂O is di-t-butyl dicarbonate, R⁶⁰ is single bondor C1-3 alkylene and the other symbols are the same meanings as definedhereinbefore.

The reactions described in the above-mentioned Schemes may be carriedout by known methods. In the above-mentioned Schemes, compounds used forstarting materials are may be known per se or may be easily prepared byknown methods.

In the present invention, the other starting materials and each reagentare known per se or may be prepared by known methods.

In each reaction in the present specification, products may be purifiedby a conventional manner. For example, it may be carried out bydistillation at atmospheric or reduced pressure, high performance liquidchromatography, thin layer chromatography or column chromatography usingsilica gel or magnesium silicate, washing or recrystallization.Purification may be carried out after each reaction or after a series ofreactions.

[Pharmacological Activity]

It has been confirmed that the compounds of the present invention of theformula (I) possess an inhibitory action on N-type calcium channelaccording to the following experiment.

Determination of Inhibitory Activity on N-type Calcium Channel:

Cell line was differentiated according to the method described in FEBSLett. (1988) 235 178-182. The cell was loaded with fluoriescent reagent,Fura-2 AM (at the final concentration of 10 μM), at 37° C. for 30minutes and suspended in Krebs-buffer containing HEPES (25 mM) to obtainthe cell suspension. The obtained cell suspension was incubated in thepresence or absence of the compounds of the present invention withnifedipine for 5 minutes. The cell was depolarized by adding potassiumchloride solution (at the final concentration of 80 mM) thereto and thena fluorescence intensity at the emission wavelength of 500 nm excited bythe UV of 340 nm and 380 nm alternately was measured using theintracellular calcium analyzer (Nippon Bunko Co., CAF-110). Theinhibitory activity of the compound of the present invention (at thefinal concentration of 3 μM) on calcium influx into the cell wascalculated from the difference in changing the fluorescence intensity atpeak (ΔR) according to the following equation. $\begin{matrix}{{Inhibitory}\quad{effect}\quad(\%)\quad{of}\quad{the}\quad{compound}\quad{of}\quad{the}} \\{{present}\quad{invention}\quad\left( {3\quad µ\quad M} \right)\quad{on}\quad{calcium}\quad{flow}}\end{matrix} = {\left( {1 - \frac{\begin{matrix}{{Mean}\quad{of}\quad\Delta\quad R\quad{in}\quad{case}\quad{of}\quad a\quad{solution}} \\{{containing}\quad{the}\quad{compound}\quad{of}\quad{the}\quad{present}\quad{invention}}\end{matrix}}{\begin{matrix}{{Mean}\quad{of}\quad\Delta\quad R\quad{in}\quad{case}\quad{of}\quad a\quad{solution}} \\{{not}\quad{containing}\quad{the}\quad{compound}\quad{of}\quad{the}\quad{present}\quad{invention}}\end{matrix}\quad}} \right) \times 100}$

The results were shown in Table 41.

TABLE 41 Inhibitory effect Example No. on calcium flow (%) 11    81 11(2) 89

From the results of an experiment using the patch-clamp techniquedescribed in Pflugers Arch. (1981) 391 85-100, the compounds of thepresent invention at the concentration of 10 μM showed clearly aninhibitory action on flux of barium ion (calcium current) passed throughan N-type calcium channel. The cells used in this experiment had beenincubated according to the method described in FEBS Lett. (1988) 235178-182.

[Toxicity]

The toxicity of the compounds of the present invention is very low andtherefore, it may be considered that the compounds of the presentinvention are safe for pharmaceutical use.

INDUSTRIAL APPLICATION

[Application for Pharmaceuticals]

The compounds of the formula (I) possess an inhibitory action on N-typecalcium channel, so they are useful as agent for the prevention and/ortreatment of cerebral infarct, transient ischemic attack,encephaloriyelopathy after cardiac operation, spinal angiopathy,hypertension with stress, neurosis, epilepsy, asthma and pollakiuriaetc. or agent for the treatment of pain (for example, acute pain,chronic pain, pain after operation, cancer pain, neuralgia, pain causedby infection etc.).

For the purpose above described, the compounds of the present inventionof the formula (I), non-toxic salts and acid addition salts thereof andhydrates thereof may be normally administered systematically or locally,usually by oral or parenteral administration.

The doses to be administered are determined depending upon age, bodyweight, symptom, the desired therapeutic effect, the route ofadministration, and the duration of the treatment etc. In the humanadult, the doses per person per dose are generally between 1 mg and 1000mg, by oral administration, up to several times per day, and between 0.1mg and 100 mg, by parenteral administration (preferred into vein) up toseveral times per day, or continuous administration between 1 and 24hrs. per day into vein.

As mentioned above, the doses to be used depend upon various conditions.Therefore, there are cases in which doses lower than or greater than theranges specified above may be used.

The compounds of the present invention may be administered as innersolid compositions or inner liquid compositions for oral administration,or as injections, liniments or suppositories etc. for parenteraladministration.

Inner solid compositions for oral administration include compressedtablets, pills, capsules, dispersible powders and granules etc. Capsulescontain hard capsules and soft capsules.

In such inner solid compositions, one or more of the active compound(s)is or are, admixed with at least one inert diluent (lactose, mannitol,glucose, microcrystalline cellulose, starch etc.), connecting agents(hydroxypropyl cellulose, polyvinylpyrrolidone, magnesium metasilicatealuminate etc.), disintegrating agents (cellulose calcium glycolateetc.), lubricating agents (magnesium stearate etc.), stabilizing agents,assisting agents for dissolving (glutamic acid, asparaginic acid etc.)etc. to prepare pharmaceuticals by known methods. The pharmaceuticalsmay, if desired, be coated with material such as sugar, gelatin,hydroxypropyl cellulose or hydroxypropyl cellulose phthalate etc., or becoated with two or more films. And further, coating may includecontainment within capsules of absorbable materials such as gelatin.

Inner liquid compositions for oral administration includepharmaceutically acceptable water-agents, suspensions, emulsions, syrupsand elixirs etc. In such liquid compositions, one or more of the activecompound(s) is or are comprised in inert diluent(s) commonly used in theart (purified water, ethanol or mixture thereof etc.). Besides inertdiluents, such compositions may also comprise adjuvants such as wettingagents, suspending agents, emulsifying agents, sweetening agents,flavoring agents, perfuming agents, preserving agents and buffer agentsetc.

Injections for parenteral administration include solutions, suspensionsand emulsions and solid injections which are dissolved or suspended insolvent when it is used. One or more active compound(s) is or aredissolved, suspended or emulsified in a solvent when such compositionsare used. Aqueous solutions or suspensions include distilled water forinjection and physiological salt solution plant oil, propylene glycol,polyethylene glycol and alcohol such as ethanol etc., and mixturethereof. Such compositions may comprise additional diluents such asstabilizing agent, assisting agents for dissolving (glutamic acid,asparaginic acid, POLYSOLBATE80 (registered trade mark) etc.),suspending agents, emulsifying agents, dispersing agents, buffer agents,preserving agents etc. They may be sterilized for example, by filtrationthrough a bacteria-retaining filter, by incorporation of sterilizingagents in the compositions or by irradiation. They may also bemanufactured in the form of sterile solid compositions and which can bedissolved in sterile water or some other sterile diluent for injectionimmediately before use.

Other compositions for parenteral administration include liquids forexternal use, ointments, endermic liniments, aerosols, spraycompositions, suppositories and pessaries for vaginal administrationetc. which comprise one or more of the active compound(s) and may beprepared by known methods.

Spray compositions may comprise additional substances other than inertdiluents: e.g. stabilizing agents such as sodium hydrogen sulfate,stabilizing agents to give isotonicity, isotonic buffer such as sodiumchloride, sodium citrate, citric acid. For preparation of such spraycompositions, for example, the method described in the U.S. Pat. Nos.2,868,691 or 3,095,355 may be used.

BEST MODE FOR CARRYING OUT THE INVENTION

The following Reference Examples and Examples are intended toillustrate, but do not limit the present invention.

The solvents in parenthesis show the developing or eluting solvents andthe ratios of the solvents used are by volume in chromatographicseparations and TLC.

The solvents in parentheses in NMR show the solvents used formeasurement.

REFERENCE EXAMPLE 1(2R)-2-t-butoxycarbonylamino-3-cyclohexylmethylthiopropanoic acid

To a solution of L-cystein (133 mg) in ethanol (10 ml), an aqueoussolution of 2N—NaOH (1.1 ml) and (bromomethyl)cyclohexane (0.17 ml) wereadded. The mixture was stirred for 2.5 hours at room temperature. To thereaction mixture, an aqueous solution of 2N—NaOH (0.6 ml) and di-t-butyldicarbonate (0.28 ml) were added. The mixture was stirred for 1 hour.After ethanol was distilled off, the mixture was acidified by additionof 1N—HCl and extracted with ethyl acetate. The extract was washed bysaturated solution of sodium chloride, dried over anhydrous magnesiumsulfate and concentrated. The residue was purified with columnchromatography on silica gel (chloroform: methanol=19:1) to obtain thetitle compound (135 mg) having the following physical data.

TLC: Rf 0.21 (ethyl acetate:acetic acid:water=9:1:1);

NMR(CDCl₃): δ 4.42-4.28 (1H, m), 3.01 (1H, dd, J=14.2, 5.2 Hz), 2.92(1H, dd, J=14.2, 3.4 Hz), 2.45 (2H, d, J=7.0 Hz), 1.91-0.81 (20H, m).

REFERENCE EXAMPLE 2(2R)-N-(4-phenoxybenzyl)-2-t-butoxycarbonylamino-3-cyclohexylmethylthiopropanamide

To a solution of a compound prepared in Reference Example 1 (4.64 g),4-phenoxybenzylamine.hydrochloride (3.51 g) and triethylamine (2.1 ml)in methylene chloride (50 ml), 1-hydroxybenzotriazole (2.91 g) and1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide.hydrochloride (3.63 g)were added under cooling with ice successively. The mixture was stirredfor 5 hours. The reaction mixture was washed by saturated solution ofsodium hydrogen carbonate, 1N HCl, water and saturated solution ofsodium chloride, successively, dried over anhydrous magnesium sulfateand concentrated. The residue was purified with column chromatography onsilica gel (ethyl acetate:hexane=1:4) to obtain the title compound (5.26g) having the following physical data.

TLC: Rf 0.67 (ethyl acetate:hexane=1:2);

NMR(CDCl₃): δ 7.39-7.22 (m, 4H), 7.15-7.06 (m, 1H), 7.03-6.93 (m, 4H),6.70 (t, J=5.3 Hz, 1H), 5.35 (d, J=6.8 Hz, 1H), 4.44 (d, J=6.0 Hz, 2H),4.30-4.20 (m, 1H), 2.99 (dd, J=14.0, 5.6 Hz, 1H), 2.83 (dd, J=14.0, 7.0Hz, 1H), 2.52-2.36 (m, 2H), 1.88-0.79 (m, 20H).

REFERENCE EXAMPLE 3(2R)-N-(4-phenoxybenzyl)-2-amino-3-cyclohexylmethylthiopropanamidehydrochloride

To a solution of a compound prepared in Reference Example 2 (5.24 g) indioxane (10 ml), a solution of 4N HCl-dioxane (50 ml) was added at roomtemperature. The mixture was stirred for 1 hour at room temperature. Thereaction mixture was concentrated to obtain the crude title compound(4.36 g). The obtained crude compound was used in the next reactionwithout purification.

REFERENCE EXAMPLE 4(2R)-N-(4-phenoxybenzyl)-3-cyclohexylmethylthio-2-((4R)-3-t-butoxycarbonylthiazolidin-4-ylcarbonylamino)propanamide

To a solution of a compound prepared in Reference Example 3 (814 mg),(4R)-3-t-butoxycarbonylthiazolidin-4-yl carboxylic acid (459 mg) andtriethylamine (0.27 ml) in methylene chloride, 1-hydroxybenzotriazoleand 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide.hydrochloride (431mg) were added under cooling with ice successively. The mixture wasstirred for 4 hours. The reaction mixture was washed by saturatedsolution of sodium hydrogen carbonate, 1N HCl, water and saturatedsolution of sodium chloride, successively, dried over anhydrousmagnesium sulfate and concentrated. The residue was purified with columnchromatography on silica gel (ethyl acetate:chloroform=1:9) to obtainthe title compound (1.08 g) having the following physical data.

TLC: Rf 0.58 (ethyl acetate:hexane=1:1);

NMR(CDCl₃): δ 7.36-7.23 (5H, m), 7.15-7.07 (2H, m), 7.01-6.91 (4H, m),4.65-4.32 (6H, m), 3.33-3.13 (3H, m), 2.79 (1H, dd, J=14.1, 6.3 Hz),2.45-2.30 (2H, m), 1.83-0.78 (20H, m).

REFERENCE EXAMPLE 5(2R)-N-(4-phenoxybenzyl)-3-cyclohexylmethylthio-2-((4R)-thiazolidin-4-ylcarbonylamino)propanamide.hydrochloride

To a compound prepared in Reference Example 4 (322 mg), a solution of 4NHCl-dioxane (3 ml) was added at room temperature. The mixture wasstirred for 1 hour. The reaction mixture was concentrated to obtain thetitle compound (263 mg) having the following physical data.

TLC: Rf 0.65 (ethyl acetate);

NMR(CD₃OD): δ 8.71 (1H, t, J=5.7 Hz), 7.36-7.28 (4H, m), 7.09 (1H, t,J=7.2 Hz), 6.96-6.89 (4H, m), 4.59-4.51 (2H, m), 4.44-4.30 (4H, m), 3.55(1H, dd, J=11.7, 7.5 Hz), 3.24 (1H, dd, J=11.7, 6.9 Hz), 2.93 (1H, dd,J=13.5, 6.3 Hz), 2.81 (1H, dd, J=13.5, 7.5 Hz), 2.46 (1H, dd, J=12.6,6.9 Hz), 2.42 (1H, dd, J=12.6, 6.6 Hz), 1.88-1.79 (2H, m), 1.74-1.61(3H, m), 1.53-1.36 (1H, m), 1.31-1.08 (3H, m), 1.00-0.88 (2H, m).

REFERENCE EXAMPLE 6(2R)-N-(4-phenoxybenzyl)-3-cyclohexylmethylthio-2-((4R)-thiazolidin-4-ylcarbonylamino)propanamide

A solution of a compound prepared in Reference Example 5 (107 mg) inethyl acetate (10 ml) was washed by saturated solution of sodiumhydrogen carbonate (5 ml) and saturated solution of sodium chloride,successively, dried over anhydrous magnesium sulfate and concentrated toobtain the title compound (96 mg) having the following physical data.

TLC: Rf 0.39 (ethyl acetate:hexane=1:1);

NMR(CDCl₃): δ 7.88 (d, J=7.5 Hz, 1H), 7.37-7.30 (m, 2H), 7.25-7.21 (m,2H), 7.14-7.08 (m, 1H), 7.02-6.94 (m, 4H), 6.84-6.80 (m, 1H), 4.49-4.36(m, 3H), 4.26 (d, J=9.9 Hz, 1H), 4.19-4.15 (m, 1H), 4.05 (d, J=9.9 Hz,1H), 3.42 (dd, J=11.1, 4.2 Hz, 1H), 3.10 (dd, J=11.1, 7.5 Hz, 1H), 2.93(dd, J=13.8, 6.3 Hz, 2H), 2.83 (dd, J=13.8, 7.2 Hz, m), 2.45 (d, J=6.6Hz, 2H), 1.86-1.58 (m, 5H), 1.51-1.36 (m, 1H), 1.29-1.05 (3H, m),0.98-0.85 (m, 2H).

EXAMPLE 1(2R)-N-(4-phenoxybenzyl)-3-cyclohexylmethylthio-2-((4R)-3-methoxymethylcarbonylthiazolidin-4-ylcarbonylamino)propanamide

A compound prepared in Reference Example 6 (170 mg) and triethylamine(55 μl) were dissolved into methylene chloride (4 ml). Thereto,methoxyacetyl chloride (37 μl) was added. The mixture was stirred for2.5 hours at room temperature. The reaction mixture was concentrated.The residue was purified with column chromatography on silica gel(chloroform:methanol=50:1) to obtain the compound (172 mg) of thepresent invention having the following physical data.

TLC: Rf 0.44 (chloroform:methanol=19:1);

NMR(DMSO-d₆): δ 8.11 (br, 1H), 7.89 (br, 1H), 7.38-7.34 (m, 2H),7.29-7.27 (m, 2H), 7.13-7.09 (m, 1H), 6.99-6.93 (m, 4H), 4.89 (dd,J=7.5, 4.0 Hz, 1H), 4.78 (d, J=9.5 Hz, 1H), 4.48-4.42 (m, 2H), 4.29 (d,J=6.0 Hz, 2H), 4.12-4.01 (m, 2H), 3.30 (s, 3H), 3.34-3.27 (m, 1H),3.17-3.07 (m, 1H), 2.89 (dd, J=13.5, 6.3 Hz, 1H), 2.76 (dd, J=13.5, 7.5Hz, 1H), 246-2.39 (m, 2H), 1.78-1.72 (m, 2H), 1.68-1.56 (m, 3H),1.47-1.38 (m, 1H), 1.26-1.08 (m, 3H), 0.99-0.90 (m, 2H).

EXAMPLE 1 (1)˜EXAMPLE 1 (14)

By the same procedure described in Example 1, using a compound preparedin Reference Example 6 and(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-((4R)-thiazolidin-4-ylcarbonylamino)propanamide,(2R)-N-(4-nitrobenzyl)-3-cyclohexylmethylthio-2-((4R)-thiazolidin-4-ylcarbonylamino)propanamideand(2R)-N-(1-benzylpiperidin-4-yl)-3-cyclohexylmethylthio-2-((4R)-thiazolidin-4-ylcarbonylamino)propanamideprepared by the same procedures described in Reference Example1→Reference Example 2→Reference Example 3→Reference Example 4→ReferenceExample 5→Reference Example 6, the following compounds of the presentinvention were obtained.

EXAMPLE 1 (1)(2R)-N-(4-nitrobenzyl)-3-cyclohexylmethylthio-2-((4R)-3-(dimethylaminomethylcarbonyl)thiazolidin-4-ylcarbonylamino)propanamide

TLC: Rf 0.45 (methanol:chloroform=5:95);

NMR(CDCl₃): δ 8.17 (2H, d, J=8.5 Hz), 7.49-7.44 (3H, m), 6.98 (1H, d,J=7.5 Hz), 4.88 (1H, d, J=9.5 Hz), 4.83 (1H, t, J=6.0 Hz), 4.80 (1H, d,J=9.5 Hz), 4.65-4.61 (1H, m), 4.58 (1H, dd, J=15.5, 6.0 Hz), 4.49 (1H,dd, J=15.5, 5.5 Hz), 3.30 (2H, d, J=6.0 Hz), 3.23 (1H, dd, J=14.0, 5.0Hz), 3.20 (1H, d, J=6.0 Hz), 3.12 (1H, d, J=14.5 Hz), 2.82 (1H, dd,J=14.0, 5.5 Hz), 2.38 (1H, dd, J=13.0, 7.0 Hz), 2.30 (1H, dd, J=13.0,6.5 Hz), 2.28 (6H, s), 1.82-1.62 (5H, m), 1.46-1.34 (1H, m), 1.27-1.06(3H, m), 0.98-0.80 (2H, m).

EXAMPLE 1 (2)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-((4R)-3-acetyloxymethylcarbonylthiazolidin-4-ylcarbonylamino)propanamide

TLC: Rf 0.45 (hexane:ethyl acetate=1:8);

NMR(CD₃OD): δ 7.24-7.19 (m, 2H), 6.87-6.83 (m, 2H), 4.95-4.40 (m, 6H),4.36 (d, J=16.0 Hz, 1H), 4.26 (d, J=16.0 Hz, 1H), 3.76 (s, 3H),3.40-3.30 (m, 1H), 3.19-3.10 (m, 1H), 2.97 (dd, J=14.0, 6.2 Hz, 1H),2.77 (dd, J=14.0, 8.4 Hz, 1H), 2.41 (d, J=7.0 Hz, 2H), 2.08 (s, 3H),1.90-1.55 (m, 5H), 1.55-0.80 (m, 6H).

EXAMPLE 1 (3)(2R)-N-(1-benzylpiperidin-4-yl)-3-cyclohexylmethylthio-2-((4R)-3-(pyridin-3-ylcarbonyl)thiazolidin-4-ylcarbonylamino)propanamide

TLC: Rf 0.43 (chloroform:methanol=9:1);

NMR(CD₃OD): δ 8.85-8.64 (m, 2H), 8.15-7.95 (m, 1H), 7.60-7.45 (m, 1H),7.33-7.18 (m, 5H), 5.10-4.60 (m, 3H), 4.52-4.35 (m, 1H), 3.75-3.35 (m,2H), 3.51 (s, 2H), 3.30-3.17 (m, 1H), 3.00-2.70 (m, 4H), 2.44 (d, J=6.6Hz, 2H), 2.22-2.04 (m, 2H), 1.90-0.081 (m, 15H).

EXAMPLE 1 (4)(2R)-N-(1-benzylpiperidin-4-yl)-3-cyclohexylmethylthio-2-((4R)-3-acetyloxymethylcarbonylthiazolidin-4-ylcarbonylamino)propanamide

NMR(CD₃OD): δ 7.37-7.23 (m, 5H), 4.90-4.35 (m, 6H), 3.79-3.60 (m, 1H),3.64 (s, 2H), 3.45-3.31 (m, 1H), 3.22-3.09 (m, 1H), 3.04-2.84 (m, 3H),2.75 (dd, J=13.7, 8.7 Hz, 1H), 2.44 (d, J=6.6 Hz, 2H), 2.37-2.20 (m,2H), 2.11 (s, 3H), 1.96-0.82 (m, 15H).

EXAMPLE 1 (5)(2R)-N-(4-phenoxybenzyl)-3-cyclohexylmethylthio-2-((4R)-3-acetyloxymethylcarbonylthiazolidin-4-ylcarbonylamino)propanamide

TLC: Rf 0.56 (chloroform:methanol=19:1);

NMR(CD₃OD): δ 7.37-7.27 (m, 4H), 7.13-7.02 (m, 1H), 7.00-6.87 (m, 4H),4.90-4.44 (m, 6H), 4.41 (d, J=15.6 Hz, 1H), 4.12 (d, J=15.6 Hz, 1H),4.42-3.30 (m, 1H), 3.20-3.10 (m, 1H), 2.98 (dd, J=13.8, 6.2 Hz, 1H),2.79 (dd, J=13.8, 8.2 Hz, 1H), 2.43 (d, J=7.0 Hz, 2H), 2.08 (s, 3H),1.90-0.80 (m, 11H).

EXAMPLE 1 (6)(2R)-N-(4-phenoxybenzyl)-3-cyclohexylmethylthio-2-((4R)-3-(2-methoxyethoxymethylcarbonyl)thiazolidin-4-ylcarbonylamino)propanamide

TLC: Rf 0.48 (chloroform:methanol=19:1);

NMR(CD₃OD): δ 7.38-7.25 (m, 4H), 7.13-7.04 (m, 1H), 6.98-6.88 (m, 4H),4.87-4.10 (m, 8H), 3.70-3.58 (m, 2H), 3.58-3.48 (m, 2H), 3.40-3.30 (m,1H), 3.33 (s, 3H), 3.16-2.92 (m, 2H), 2.80 (dd, J=13.6, 8.0 Hz, 1H),2.42 (d, J=7.0 Hz, 2H), 1.90-0.80 (m, 11H).

EXAMPLE 1 (7)(2R)-N-(4-phenoxybenzyl)-3-cyclohexylmethylthio-2-((4R)-3-(pyridin-3-ylcarbonyl)thiazolidin-4-ylcarbonylamino)propanamide

TLC: Rf 0.52 (chloroform:methanol=19:1);

NMR(CD₃OD): δ 8.84-8.70 (m, 1H), 8.69-8.63 (m, 1H), 8.11-7.95 (m, 1H),7.58-7.44 (m, 1H), 7.38-7.25 (m, 4H), 7.13-7.05 (m, 1H), 6.97-6.86 (m,4H), 5.10-4.41 (m, 4H), 4.37 (s, 2H), 3.51-3.40 (m, 1H), 3.26-3.17 (m,1H). 3.10-2.70 (m, 2H), 2.42 (d, J=7.0 Hz, 2H), 1.90-0.80 (m, 11H).

EXAMPLE 1 (8)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-((4R)-3-(2-methoxyacetyl)thiazolidin-4-ylcarbonylamino)propanamide

TLC Rf 0.43 (chloroform:methanol=14:1);

NMR(DMSO-d₆): δ 8.05 (brs, 1H), 7.88 (brs, 1H), 7.20-7.17 (m, 2H),6.87-6.84 (m, 2H), 4.89 (dd, J=7.5, 4.0 Hz, 1H), 4.79 (d, J=9.5 Hz, 1H),4.46-4.41 (m, 2H), 4.23 (d, J=6.0 Hz, 2H), 4.11 (d, J=15.0 Hz, 1H),4.06-4.01 (m, 1H), 3.74 (s, 3H), 3.33-3.28 (m, 1H), 3.31 (s, 3H),3.15-3.11 (m, 1H), 2.88 (dd, J=13.5, 5.8 Hz, 1H), 2.75 (dd, J=13.5, 7.8Hz, 1H), 2.42 (d, J=6.0 Hz, 2H), 1.79-1.70 (m, 2H), 1.70-1.56 (m, 3H),1.47-1.37 (m, 1H), 1.27-1.10 (m, 3H), 1.00-0.89 (m, 2H).

EXAMPLE 1 (9)(2R)-N-(1-benzylpiperidin-4-yl)-3-cyclohexylmethylthio-2-((4R)-3-(2-methoxyacetyl)thiazolidin-4-ylcarbonylamino)propanamide

TLC: Rf 0.36 (chloroform:methanol=14:1);

NMR(DMSO-d₆): δ 7.80 (brs, 1H), 7.44 (brs, 1H), 7.32-7.26 (m, 4H),7.24-7.20 (m, 1H), 4.87 (dd, J=7.3, 4.3 Hz, 1H), 4.79 (d, J=9.5 Hz, 1H),4.46 (d, J=9.5 Hz, 1H), 4.39-4.34 (m, 1H), 4.12 (d, J=14.0 Hz, 1H),4.08-4.02 (m, 1H), 3.60-3.51 (m, 1H), 3.46 (s, 2H), 3.33 (s, 3H), 3.31(dd, J=11.8, 7.3 Hz, 1H), 3.13 (dd, J=11.8, 4.3 Hz, 1H), 2.85 (dd,J=13.0, 6.3 Hz, 1H), 2.72 (dd, J=13.0, 8.0 Hz, 1H), 2.76-2.70 (m, 2H),2.43 (d, J=6.5 Hz, 2H), 2.11-2.05 (m, 2H), 1.80-1.56 (m, 7H), 1.52-1.38(m, 3H), 1.27-1.09 (m, 3H), 1.00-0.90 (m, 2H).

EXAMPLE 1 (10)(2R)-N-(1-benzylpiperidin-4-yl)-3-cyclohexylmethylthio-2-((4R)-3-allyloxycarbonylthiazolidin-4-ylcarbonylamino)propanamide

TLC: Rf 0.48 (chloroform:methanol=9:1);

NMR(CD₃OD): δ 7.33-7.22 (m, 5H), 6.05-5.85 (br, 1H), 5.38-5.14 (br, 2H),4.72-4.49 (m, 5H), 4.45 (dd, J=7.8, 6.3 Hz, 1H), 3.70-3.60 (m, 1H), 3.52(s, 2H), 3.39 (dd, J=11.7, 7.2 Hz, 1H), 3.16 (dd, J=11.7, 4.8 Hz, 1H),2.99-2.69 (br, 4H), 2.44 (d, J=7.2 Hz, 2H), 2.17-2.09 (m, 2H), 1.85-1.36(m, 10H), 1.33-1.09 (m, 3H), 1.01-0.87 (m, 2H).

EXAMPLE 1 (11)(2R)-N-(4-phenoxybenzyl)-3-cyclohexylmethylthio-2-((4R)-3-allyloxycarbonylthiazolidin-4-ylcarbonylamino)propanamide

TLC: Rf 0.26 (hexane:ethyl acetate=2:1);

NMR(CDCl₃): δ 7.37-6.93 (m, 11H), 5.93-5.80 (m, 1H), 5.32-5.21 (m, 2H),4.74-4.28 (m, 8H), 3.32 (dd, J=12.0, 3.9 Hz, 1H), 3.29 (dd, J=12.0, 6.6Hz, 1H), 3.22-3.04 (br, 1H), 2.81 (dd, J=14.1, 6.6 Hz, 1H), 2.47-2.34(m, 2H), 1.80-1.52 (m, 5H), 1.48-1.04 (m, 4H), 0.96-0.80 (m, 2H).

EXAMPLE 1 (12)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-((4R)-3-allyloxycarbonylthiazolidin-4-ylcarbonylamino)propanamide

TLC: Rf 0.39 (hexane:ethyl acetate=1:1);

NMR(CDCl₃): δ 7.20 (d, J=8.7 Hz, 2H), 7.08 (d, J=7.8 Hz, 2H), 6.84 (d,J=8.7 Hz, 2H), 5.92-5.79 (m, 1H), 5.30-5.20 (m, 2H), 4.73-4.22 (m, 8H),3.78 (s, 3H), 3.32 (dd, J=12.3, 4.2 Hz, 1H), 3.28 (dd, J=12.3, 6.6 Hz,1H), 3.23-3.05 (br, 1H), 2.80 (dd, J=13.8, 6.6 Hz, 1H), 2.46-2.32 (m,2H), 1.78-1.58 (m, 5H), 1.48-1.04 (m, 4H), 0.95-0.81 (m, 2H).

EXAMPLE 1 (13)(2R)-N-(1-benzylpiperidin-4-yl)-3-cyclohexylmethylthio-((4R)-3-(2-ethoxy-1,2-dioxoethyl)thiazolidin-4-ylcarbonylamino)propanamide

TLC: Rf 0.23 (methylene chloride:methanol=19:1).

EXAMPLE 1 (14)(2R)-N-(1-benzylpiperidin-4-yl)-3-cyclohexylmethylthio-((4R)-3-phenylsulfonylthiazolidin-4-ylcarbonylamino)propanamide

TLC: Rf 0.36 (methylene chloride:methanol=19:1);

NMR(CD₃OD): δ 7.97-7.92 (m, 2H), 7.78-7.57 (m, 3H), 7.32-7.21 (m, 5H),4.75 (d, J=10.5 Hz, 1H), 4.61 (d, J=10.5 Hz, 1H), 4.52-4.46 (m, 2H),3.74-3.64 (m, 1H), 3.51 (s, 2H), 3.18 (dd, J=12.0, 5.4 Hz, 1H),3.03-2.77 (m, 5H), 2.49-2.38 (m, 2H), 2.18-2.09 (m, 2H), 1.941.37 (m,10H), 1.33-1.08 (m, 3H), 1.00-0,87 (m, 2H).

EXAMPLE 2(2R)-N-(4-phenoxybenzyl)-3-cyclohexylmethylthio-2-((4R)-3-(3-hydroxy-3-methylbutyryl)thiazolidin-4-ylcarbonylamino)propanamide

To a solution of 3-hydroxy-3-methylbutanoic acid (106 mg) in methylenechloride (5 ml), 1-hydroxy-7-azabenzotriazole (124 mg), a compoundprepared in Reference Example 6 (231 mg) and1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide.hydrochloride (178 mg)were added under cooling with ice successively. The mixture was stirredovernight at room temperature. To the reaction mixture, saturatedsolution of sodium hydrogen carbonate (10 ml) was added. The mixture wasextracted with methylene chloride (10 ml). The extract was washed bysaturated solution of sodium chloride (15 ml), dried over anhydrousmagnesium sulfate and concentrated. The residue was purified with columnchromatography on silica gel (hexane:ethyl acetate=1:2) to obtain thecompound (174 mg) of the present invention having the following physicaldata.

TLC: Rf 0.22 (hexane:ethyl acetate=1:2);

NMR(DMSO-d₆, 100° C.): δ 8.16-8.05 (br, 1H), 7.92-7.76 (br, 1H),7.38-7.34 (m, 2H), 7.28 (d, J=9.0 Hz, 2H), 7.11 (t, J=7.5 Hz, 1H),6.99-6.92 (m, 4H), 4.97-4.90 (br, 1H), 4.85 (d, J=8.5 Hz, 1H), 4.61-4.41(br, 2H), 4.29 (d, J=6.0 Hz, 2H), 3.34-3.26 (br, 1H), 3.18-3.12 (m, 1H),2.89 (dd, J=13.0, 5.5 Hz, 1H), 2.75 (dd, J=13.0, 7.0 Hz, 1H), 2.57-2.40(m, 4H), 1.77-1.74 (m, 2H), 1.68-1.57 (m, 3H), 1.47-1.38 (m, 1H),1.26-1.09 (m, 9H), 0.98-0.91 (m, 2H).

EXAMPLE 2 (1)˜EXAMPLE 2 (7)

By the same procedure described in Example 2, using a compound preparedin Reference Example 6 and(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-((4R)-thiazolidin-4-ylcarbonylamino)propanamideand(2R)-N-(1-benzylpiperidin-4-y)-3-cyclohexylmethylthio-2-((4R)-thiazolidin-4-ylcarbonylamino)propanamideprepared by the same procedures described in Reference Example1→Reference Example 2→Reference Example 3→Reference Example 4→ReferenceExample 5→Reference Example 6, the following compounds of the presentinvention were obtained.

EXAMPLE 2 (1)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-((4R)-3-(2-hydroxy-2-methylpropionyl)thiazolidin-4-ylcarbonylamino)propanamide

TLC: Rf 0.45 (chloroform:methanol=14:1);

NMR(CD₃OD): δ 7.23-7.20 (2H, m), 6.87-6.83 (2H, m), 5.42-5.18 (1H, m),4.93-4.62 (2H, m), 4.49-4.45 (1H, m), 4.40-4.23 (2H, m), 3.76 (3H, s),3.38-2.80 (4H, m), 2.39 (2H, d, J=6.9 Hz), 1.84-1.59 (5H, m), 1.50-1.07(4H, m), 1.39 (3H, s), 1.37 (3H, s), 0.98-0.83 (2H, m).

EXAMPLE 2 (2)(2R)-N-(1-benzylpiperidin-4-yl)-3-cyclohexylmethylthio-2-((4R)-3-dimethylaminomethylcarbonylthiazolidin-4-ylcarbonylamino)propanamide

TLC: Rf 0.38 (chloroform:methanol=9:1);

NMR(CD₃OD): δ 7.35-7.20 (m, 5H), 5.16-4.63 (m, 4H), 4.54-4.35 (m, 2H),3.73-3.55 (m, 1H), 3.52 (s, 2H), 3.45-3.05 (m, 2H), 2.962.70 (m, 4H),2.47-2.40 (m, 2H), 2.32 and 2.27 (s, 6H), 2.23-2.05 (m, 2H), 1.90-0.80(m, 15H).

EXAMPLE 2 (3)(2R)-N-(1-benzylpiperidin-4-yl)-3-cyclohexylmethylthio-2-((4R)-3-(morpholin-4-ylmethylcarbonyl)thiazolidin-4-ylcarbonylamino)propanamide

TLC: Rf 0.52 (chloroform:methanol=9:1);

NMR(DMSO-d₆): δ 7.60 (br, 1H), 7.36-7.20 (m, 6H), 5.03-4.96 (m, 1H),4.92 (d, J=9.5 Hz, 1H), 4.56-4.50 (m, 1H), 4.40-4.35 (m, 1H), 3.63-3.54(m, 5H), 3.49 (s, 2H), 3.32-3.25 (m, 2H), 3.18-3.14 (m, 2H), 2.86 (dd,J=13.5, 6.0 Hz, 1H), 2.80-2.72 (m, 3H), 2.56-2.44 (m, 4H), 2.44 (d,J=7.0 Hz, 2H), 2.16-2.09 (m, 2H), 1.80-1.56 (m, 7H), 1.56-1.37 (m, 3H),1.28-1.10 (m, 3H), 1.04-0.93 (m, 2H).

EXAMPLE 2 (4)(2R)-N-(1-benzylpiperidin-4-yl)-3-cyclohexylmethylthio-2-((4R)-3-(3-hydroxy-3-methylbutyryl)thiazolidin-4-ylcarbonylamino)propanamide

TLC: Rf 0.63 (chloroform:methanol=9:1);

NMR(DMSO-d₆): δ 7.63 (br, 1H), 7.34-7.20 (m, 6H), 4.94 (dd, J=7.2, 4.0Hz, 1H), 4.86 (d, J=8.5 Hz, 1H), 4.58-4.50 (m, 1H), 4.40-4.33 (m, 2H),3.62-3.53 (m, 1H), 3.49 (s, 2H), 3.31 (dd, J=12.0, 7.2 Hz, 1H), 3.17(dd, J=12.0, 4.0 Hz, 1H), 2.86 (dd, J=13.0, 6.0 Hz, 1H), 2.78-2.72 (m,3H), 2.63-2.53 (m, 2H), 2.45 (d, J=6.5 Hz, 2H), 2.16-2.10 (m, 2H),1.80-1.56 (m, 7H), 1.56-1.40 (m, 3H), 1.30-1.10 (m, 3H), 1.25 (s, 6H),1.03-0.94 (m, 2H).

EXAMPLE 2 (5)(2R)-N-(4-phenoxybenzyl)-3-cyclohexylmethylthio-2-((4R)-3-(2-dimethylaminoacetyl)thiazolidin-4-ylcarbonylamino)propanamide

TLC: Rf 0.44 (chloroform:methanol=9:1);

NMR(DMSO-d₆): δ 8.63-8.45 and 8.16-8.14 (m, 2H), 7.39-7.25 (m, 4H),7.13-7.08 (m, 1H), 6.97-6.92 (m, 4H), 5.17-5.14 and 4.91-4.74 (m, 2H),4.564.21 (m, 4H), 3.38-3.14 (m, 2H), 3.05-2.92 (m, 2H), 2.85-2.76 (m,1H), 2.70-2.59 (m, 1H), 2.43-2.34 (m, 2H), 2.16-2.14 (m, 6H), 1.74-1.54(m, 5H), 1.43-1.29 (m, 1H), 1.21-0.99 (m, 3H), 0.92-0.79 (m, 2H).

EXAMPLE 2 (6)(2R)-N-(4-phenoxybenzyl)-3-cyclohexylmethylthio-2-((4R)-3-(2-hydroxy-2-methylpropionyl)thiazolidin-4-ylcarbonylamino)propanamide

TLC: Rf 0.28 (hexane:ethyl acetate=1:2);

NMR(DMSO-d₆, 100° C.): δ 7.38-7.33 (m, 2H), 7.28 (d, J=8.5 Hz, 2H), 7.11(t, J=7.5 Hz, 1H), 6.98-6.91 (m, 4H), 5.28 (d, J=10.0 Hz, 1H), 5.21-5.12(br, 1H), 4.54 (d, J=10.0 Hz, 1H), 4.43 (t, J=6.5 Hz, 1H), 4.28 (s, 2H),3.22 (dd, J=11.5, 7.0 Hz, 1H), 3.12 (dd, J=11.5, 4.5 Hz, 1H), 2.88 (dd,J=13.5, 6.0 Hz, 1H), 2.80 (dd, J=13.5, 7.0 Hz, 1H), 2.44-2.40 (m, 2H),1.77-1.72 (m, 2H), 1.68-1.56 (m, 3H), 1.47-1.33 (m, 7H), 0.98-0.89 (m,2H).

EXAMPLE 2 (7)(2R)-N-(4-phenoxybenzyl)-3-cyclohexylmethylthio-2-((4R)-3-(morpholin-4-ytmethylcarbonyl)thiazolidin-4-ylcarbonylamino)propanamide

TLC: Rf 0.46 (chloroform:methanol=9:1);

NMR(DMSO-d₆, 100° C.): δ 8.18-8.10 (br, 1H), 7.90-7.77 (br, 1H),7.38-7.34 (m, 2H), 7.29 (d, J=8.5 Hz, 2H), 7.11 (t, J=7.5 Hz, 1H),6.99-6.92 (m, 4H), 5.12-4.90 (br, 2H), 4.57-4.43 (br, 2H), 4.29 (d,J=6.0 Hz, 2H), 3.56 (t, J=5.0 Hz, 4H), 3.31-3.22 (m, 2H), 3.15-3.10 (m,2H), 2.88 (dd, J=13.5, 6.0 Hz, 1H), 2.76 (dd, J=13.5, 7.5 Hz, 1H),2.47-2.41 (m, 6H), 1.77-1.74 (m, 2H), 1.68-1.57 (m, 3H), 1.47-1.38 (m,1H), 1.25-1.09 (m, 3H), 0.98-0.91 (m, 2H).

EXAMPLE 3(2R)-N-(4-phenoxybenzyl)-3-cyclohexylmethylthio-2-((4R)-3-carboxymethylthiazolidin-4-ylcarbonylamino)propanamide.hydrochloride

A compound prepared in Reference Example 6 (300 mg) and 40% glyoxalicacid (1.0 ml) were dissolved into a mixture solution of methylenechloride (4 ml) and ethanol (10 ml). Thereto, sodium cyanoboro hydride(124 mg) was added. The mixture was adjustified to pH5.5 by addition ofan aqueous solution of 1N—NaOH and then stirred for 3 hours at roomtemperature. The reaction mixture was concentrated. The residue waspurified with column chromatography on silica gel(chloroform:methanol=20:1). The purified product was dissolved intoethyl acetate (5 ml). Thereto, a solution of 4N HCl-ethyl acetate (0.25ml) was added. After stirring the mixture, a solvent was distilled offto obtain the compound (260 mg) of the present invention having thefollowing physical data.

NMR(CD₃OD): δ 7.38-7.26 (m, 4H), 7.13-7.04 (m, 1H), 6.97-6.88 (m, 4H),4.64 (d, J=10.6 Hz, 1H), 4.55 (dd, J=8.2, 6.0 Hz, 1H), 4.48 (dd, J=7.7,5.4 Hz, 1H), 4.38-4.32 (m, 3H), 4.12 (d, J=17.2 Hz, 1H), 4.00 (d, J=17.2Hz, 1H), 3.50 (dd, J=11.7, 7.7 Hz, 1H), 3.34 (dd, J=11.7, 5.4 Hz 1H),2.96 (dd, J=13.6, 6.0 Hz, 1H), 2.82 (dd, J=13.6, 8.2 Hz, 1H), 2.44 (d,J=6.8 Hz, 2H), 1.90-0.80 (m, 11H).

EXAMPLE 3 (1)˜EXAMPLE 3 (13)

By the same procedure described in Example 3, using a compound preparedin Reference Example 6 and(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-((4R)-thiazolidin-4-ylcarbonylamino)propanamideand(2R)-N-(1-benzylpiperidin-4-yl)-3-cyclohexylmethylthio-2-((4R)-thiazolidin-4-ylcarbonylamino)propanamideprepared by the same procedures described in Reference Example1→Reference Example 2→Reference Example 3→Reference Example 4→ReferenceExample 5→Reference Example 6 (provided that the procedure to obtainhydrochloride was not carried out), the following compounds of thepresent invention were obtained.

EXAMPLE 3 (1)(2R)-N-(4-nitrobenzyl)-3-cyclohexylmethylthio-2-((4R)-3-(3-methylbutyl)thiazolidin-4-ylcarbonylamino)propanamide

TLC: Rf 0.66 (ethyl acetate:hexane=1:1);

NMR(CDCl₃): δ 8.22-8.16 (2H, m), 7.96 (1H, d, J=7.4 Hz), 7.48-7.42 (2H,m), 7.13 (1H, t, J=6.6 Hz), 4.60 (1H, dd, J=15.8, 5.8 Hz), 4.51 (1H, dd,J=15.8, 6.4 Hz), 4.50-4.39 (1H, m), 4.11 (1H, d, J=10.4 Hz) 3.99 (1H,dd, J=10.4, 0.6 Hz), 3.90 (1H, dd, J=7.4, 2.4 Hz), 3.51 (1H, dd, J=11.0,2.4 Hz), 3.07 (1H, dd, J=11.0, 7.4 Hz), 2.96 (1H, dd, J=13.6, 6.6 Hz),2.84 (1H, dd, J=13.6, 7.0 Hz), 2.70-2.41 (4H, m), 1.88-0.80 (20H, m).

EXAMPLE 3 (2)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-((4R)-3-(2-hydroxyethyl)thiazolidin-4-ylcarbonylamino)propanamide

TLC: Rf 0.61 (chloroform methanol=9:1);

NMR(CD₃OD): δ 7.22-7.19 (2H, m), 6.87-6.84 (2H, m), 4.49 (1H, dd, J=8.6,5.1 Hz), 4.37-4.24 (3H, m), 4.11-4.06 (2H, m), 3.77-3.62 (2H, m), 3.76(3H, s), 3.42 (1H, dd, J=10.8, 2.6 Hz), 3.07 (1H, dd, J=10.8, 7.5 Hz),2.96 (1H, dd, J=14.1, 5.1 Hz), 2.80 (1H, dd, J=14.1, 8.6 Hz), 2.80-2.61(2H, m), 2.44-2.33 (2H, m), 1.80-1.60 (5H, m), 1.50-1.07 (4H, m),0.99-0.83 (2H, m).

EXAMPLE 3 (3)(2R)-N-(1-benzylpiperidin-4-yl)-3-cyclohexylmethylthio-2-((4R)-3-(2-hydroxyethyl)thiazolidin-4-ylcarbonylamino)propanamide

TLC: Rf 0.48 (chloroform:methanol=9:1);

NMR(CD₃OD): δ 7.34-7.20 (m, 5H), 4.44 (dd, J=8.4, 5.4 Hz, 1H), 4.24 (d,J=10.2 Hz, 1H), 4.09-4.04 (m, 2H), 3.80-3.57 (m, 3H), 3.52 (s, 2H), 3.39(dd, J=10.8, 2.3 Hz, 1H), 3.09 (dd, J=10.8, 7.4 Hz, 1H), 2.96-2.60 (m,6H), 2.42 (d, J=7.0 Hz, 2H), 2.20-2.04 (m, 2H), 1.90-0.82 (m, 15H).

EXAMPLE 3 (4)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-((4R)-3-(3-hydroxy-3-methylbutyl)thiazolidin-4-ylcarbonylamino)propanamide

TLC: Rf 0.40 (chloroform:methanol=19:1);

NMR(CD₃OD): δ 7.24-7.19 (m, 2H), 6.88-6.83 (m, 2H), 4.47 (dd, J=7.5, 5.7Hz, 1H), 4.39-4.23 (m, 2H), 4.20 (d, J=10.2 Hz, 1H), 4.12-4.02 (m, 2H),3.76 (s, 3H), 3.42 (dd, J=10.6, 2.6 Hz, 1H), 3.07 (dd, J=10.6, 7.6 Hz,1H), 3.00-2.60 (m, 4H), 2.38 (d, J=7.0 Hz, 2H), 1.87-0.80 (m, 13H), 1.21(s, 6H).

EXAMPLE 3 (5)(2R)-N-(1-benzylpiperidin-4-yl)-3-cyclohexylmethylthio-2-((4R)-3-(3-hydroxy-3-methylbutyl)thiazolidin-4-ylcarbonylamino)propanamide

TLC: Rf 0.69 (chloroform:methanol=9:1);

NMR(CD₃OD): δ 7.34-7.20 (m, 5H), 4.42 (dd, J=7.4, 5.6 Hz, 1H), 4.19 (d,J=10.2 Hz, 1H), 4.07-4.02 (m, 2H), 3.74-3.56 (m, 1H), 3.53 (s, 2H), 3.41(dd, J=10.6, 2.6 Hz, 1H), 3.07 (dd, J=10.6, 7.4 Hz, 1H), 2.95-2.60 (m,6H), 2.41 (d, J=7.0 Hz, 2H), 2.22-2.05 (m, 2H), 1.91-0.82 (m, 17H), 1.21(s, 6H).

EXAMPLE 3 (6)(2R)-N-(1-benzylpiperidin-4-yl)-3-cyclohexylmethylthio-2-((4R)-3-(3-hydroxypropyl)thiazolidin-4-ylcarbonylamino)propanamide

TLC: Rf 0.46 (chloroform:methanol=9:1);

NMR(CD₃OD): δ 7.35-7.20 (m, 5H), 4.42 (dd, J=7.4, 5.8 Hz, 1H), 4.21-4.16(m, 1H), 4.06-4.01 (m, 2H), 3.76-3.56 (m, 3H), 3.53 (s, 2H), 3.40 (dd,J=10.6, 2.5 Hz, 1H), 3.07 (dd, J=10.6, 7.4 Hz, 1H), 2.96-2.58 (m, 6H),2.41 (d, J=7.0 Hz, 2H), 2.21-2.05 (m, 2H), 1.90-0.82 (m, 17H).

EXAMPLE 3 (7)(2R)-N-(1-benzylpiperidin-4-yl)-3-cyclohexylmethylthio-2-((4R)-3-carboxymethylthiazolidin-4-ylcarbonylamino)propanamide

TLC: Rf 0.22 (chloroform:methanol=9:1);

NMR(CD₃OD): δ 7.55-7.43 (m, 5H), 4,47 (dd, J=8.0, 5.2 Hz, 1H), 4.28 (s,2H), 4.24 (d, J=10.2 Hz, 1H), 4.04 (d, J=10.2 Hz, 1H), 4.00-3.89 (m,2H), 3.56-3.22 (m, 6H), 3.14-2.86 (m, 4H), 2.42 (d, J=6.6 Hz, 2H),2.10-0.80 (m, 15H).

EXAMPLE 3 (8)(2R)-N-(4-phenoxybenzyl)-3-cyclohexylmethylthio-2-((4R)-3-(2-hydroxyethyl)thiazolidin-4-ylcarbonylamino)propanamide

TLC: Rf 0.41 (chloroform:methanol=19:1);

NMR(CD₃OD): δ 7.33-7.09 (m, 4H), 7.13-7.04 (m, 1H), 6.97-6.89 (m, 4H),4.50 (dd, J=8.4, 5.3 Hz, 1H), 4.36 (s, 2H), 4.26 (d, J=10.0 Hz, 1H),4.134.05 (m, 2H), 3.80-3.60 (m, 2H), 3.43 (dd, J=10.7, 2.8 Hz, 1H), 3.08(dd, J=10.7, 7.5 Hz, 1H), 2.99 (dd, J=14.0, 5.3 Hz, 1H), 2.81 (dd,J=14.0, 8.4 Hz, 1H), 2.82-2.58 (m, 2H), 2.40 (d, J=7.0 Hz, 2H),1.88-0.80 (m, 11H).

EXAMPLE 3 (9)(2R)-N-(4-phenoxybenzyl)-3-cyclohexylmethylthio-2-((4R)-3-(2,3-dihydroxypropyl)thiazolidin-4-ylcarbonylamino)propanamide

TLC: Rf 0.27 (chloroform:methanol=19 1);

NMR(CDCl₃): δ 8.27 (brt, J=9.3 Hz, 1H), 7.38-6.94 (m, 10H), 4.58-4.39(m, 3H), 4.22-4.14 (m, 1H), 4.00-3.12 (m, 7H), 3.00-2.55 (m, 4H), 2.44(d, J=7.0 Hz, 2H), 1.87-0.80 (m, 11H).

EXAMPLE 3 (10)(2R)-N-(4-phenoxybenzyl)-3-cyclohexylmethylthio-2-((4R)-3-(2-methoxyethyl)thiazolidin-4-ylcarbonylamino)propanamide

TLC: Rf 0.46 (chloroform:methanol=19:1);

NMR(CD₃OD): δ 7.38-7.26 (m, 4H), 7.14-7.05 (m, 1H), 6.97-6.90 (m, 4H),4.49 (dd, J=7.6, 5.7 Hz, 1H), 4.37 (s, 2H), 4.20 (d, J=10.0 Hz, 1H),4.12-4.06 (m, 2H), 3.61-3.54 (m, 2H), 3.42-3.35 (m, 1H), 3.34 (s, 3H),3.08 (dd, J=11.0, 7.6 Hz, 1H), 2.96 (dd, J=13.7, 5.7 Hz, 1H), 2.90-2.73(m, 3H), 2.41 (d, J=6.8 Hz, 2H), 1.90-0.80 (m, 11H).

EXAMPLE 3 (11)(2R)-N-(4-phenoxybenzyl)-3-cyclohexylmethylthio-2-((4R)-3-(2,3-dimethoxypropyl)thiazolidin-4-ylcarbonylamino)propanamide

TLC: Rf 0.63 (chloroform:methanol=19: 1);

NMR(CD₃OD): δ 7.38-7.25 (m, 4H), 7.13-7.05 (m, 1H), 6.98-6.88 (m, 4H),4.55-4.46 (m, 1H), 4.37 (s, 2H), 4.21-4.04 (m, 3H), 3.62-3.46 (m, 3H),3.42 and 3.41 (s, 3H), 3.40-3.30 (m, 1H), 3.35 and 3.34 (s, 3H),3.16-2.60 (m, 5H), 2.40 (d, J=6.6 Hz, 2H), 1.87-0.80 (m, 11H).

EXAMPLE 3 (12)(2R)-N-(4-phenoxybenzyl)-3-cyclohexylmethylthio-2-((4R)-3-(3-hydroxy-3-methylbutyl)thiazolidin-4-ylcarbonylamino)propanamide

TLC: Rf 0.51 (chloroform:methanol=19:1);

NMR(CD₃OD): δ 7.37-7.27 (m, 4H), 7.14-7.05 (m, 1H), 6.97-6.90 (m, 4H),4.48 (dd, J=7.5, 5.7 Hz, 1H), 4.40 (d, J=14.9 Hz, 1H), 4.33 (d, J=14.9Hz, 1H), 4.19 (d, J=9.9 Hz, 1H), 4.10-4.03 (m, 2H), 3.42 (dd, J=10.8,2.6 Hz, 1H), 3.07 (dd, J=10.8, 7.8 Hz, 1H), 2.97 (dd, J=13.8, 5.7 Hz,1H), 2.83 (dd, J=13.8, 7.5 Hz, 1H), 2.78-2.61 (m, 2H), 2.39 (d, J=6.9Hz, 2H), 1.21 (s, 3H), 1.20 (s, 3H), 1.86-0.84 (m, 13H).

EXAMPLE 3 (13)(2R)-N-(4-phenoxybenzyl)-3-cyclohexylmethylthio-2-((4R)-3-(3-hydroxypropyl)thiazolidin-4-ylcarbonylamino)propanamide

TLC: Rf 0.51 (chloroform:methanol=19:1);

NMR(CD₃OD): δ 7.38-7.27 (m, 4H), 7.14-7.04 (m, 1H), 6.98-6.90 (m, 4H),4.49 (dd, J=7.4, 5.6 Hz, 1H), 4.45-4.28 (m, 2H), 4.19 (d, J=10.2 Hz,1H), 4.10-4.02 (m, 2H), 3.75-3.67 (m, 2H), 3.42 (dd, J=10.7, 2.5 Hz,1H), 3.07 (dd, J=10.7, 7.6 Hz, 1H), 2.96 (dd, J=13.8, 5.6 Hz, 1H), 2.84(dd, J=13.8, 7.4 Hz, 1H), 2.76-2.57 (m, 2H), 2.39 (d, J=7.0 Hz, 2H),1.90-0.80 (m, 13H).

EXAMPLE 4(2R)-N-((1R)-1-(4-nitrophenyl)ethyl)-3-cyclohexylmethylthio-2-((4R)-3-t-butylcarbamoylthiazolidin-4-ylcarbonylamino)propanamide

A solution of(2R)-N-((1R)-1-(4-nitrophenyl)ethyl)-3-cyclohexylmethylthio-2-((4R)-thiazolidin-4-ylcarbonylamino)propanamidehydrochloride (109 mg) prepared by the same procedures described inReference Example 1→Reference Example 2→Reference Example 3→ReferenceExample 4→Reference Example 5, t-butyl isocyanate (0.027 ml) andtriethylamine (0.03 ml) in methylene chloride (3 ml) was refluxedovernight. The reaction mixture was washed by 1N HCl, water andsaturated solution of sodium chloride, successively, dried overanhydrous magnesium sulfate and concentrated. The residue was purifiedwith column chromatography on silica gel (ethyl acetate:hexane=1:2) toobtain the compound (86 mg) of the present invention having thefollowing physical data.

TLC: Rf 0.31 (ethyl acetate:hexane=1:1);

NMR(CDCl₃): δ 8.18-8.11 (2H, m), 7.78 (1H, d, J=7.4 Hz), 7.60-7.53 (2H,m), 7.22 (1H, d, J=8.8 Hz), 5.20-5.06 (1H, m), 4.75 (1H, q, J=3.2 Hz),4.65 (1H, ddd, J=8.8, 5.6, 3.6 Hz) 4.50 (1H, s), 4.43 (1H, d, J=7.4 Hz),4.38 (1H, d, J=7.4 Hz), 3.38 (1H, dd, J=12.2, 2.8 Hz), 3.29 (1H, dd,J=12.2, 6.2 Hz), 3.24 (1H, dd, J=13.6, 4.0 Hz), 2.77 (1H, dd, J=13.6,5.6 Hz), 2.23 (1H, dd, J=12.4, 6.6 Hz), 2.13 (1H, dd, J=12.4, 7.0 Hz),1.80-0.64 (23H, m).

EXAMPLE 5˜EXAMPLE 5 (10)

By the same procedure described in Reference Example 1→Reference Example2→Reference Example 3→Reference Example 4, the following compounds ofthe present invention were obtained.

With the proviso that, the compound of Example 5 (4) was prepared by theprocedure comprising oxidation after reaction of Reference Example 2.

EXAMPLE 5 (2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-((2RS)-3-t-butoxycarbonyl-1-oxothiazolidin-2-ylcarbonylamino)propanamide

TLC: Rf 0.61, 0.52 (ethyl acetate);

NMR(CD₃OD): δ 7.22-7.19 (2H, m), 6.87-6.83 (2H, m), 5.56-5.43 (1H, m),4.53-4.46 (1H, m), 4.35-4.25 (2H, m), 4.18-4.09 (2H, m), 3.76-3.75 (3H,m), 3.36-3.22 (2H, m), 3.10-2.85 (2H, m), 2.79-2.69 (1H, m), 2.46-2.34(2H, m), 1.86-0.84 (20H, m),

EXAMPLE 5 (1)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-((2RS)-3-t-butoxycarbonyl-1,1-dioxothiazolidin-2-ylcarbonylamino)propanamide

TLC: Rf 0.59 (methylene chloride:ethyl acetate=3:1);

NMR(CD₃OD): δ 7.25-7.18 (2H, m), 6.87-6.80 (2H, m), 5.16-5.07 (1H, m),4.58-4.50 (1H, m), 4.33-4.30 (2H, m), 4.07-3.96 (1H, m), 3.86-3.68 (1H,m), 3.75 (3H, s), 3.60-3.20 (2H, m), 3.07-2.73 (2H, m), 2.42 (2H, d,J=7.0 Hz), 1.89-1.60 (5H, m), 1.50-1.11 (4H, m), 1.46-1.39 (9H, m),1.01-0.82 (2H, m).

EXAMPLE 5 (2)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-((4R)-3-t-butoxycarbonyl-1,1-dioxothiazolidin-4-ylcarbonylamino)propanamide

TLC: Rf 0.53 (methylene chloride:ethyl acetate=3:1);

NMR(CD₃OD): δ 7.24-7.19 (2H, m), 6.88-6.83 (2H, m), 5.07-4.85 (1H, m),4.75 (1H, dd, J=12.0, 1.7 Hz), 4.49 (1H, t, J=6.8 Hz), 4.37-4.30 (3H,m), 3.76 (3H, s), 3.75-3.50 (1H, m), 3.50-3.30 (1H, m), 2.97-2.73 (2H,m), 2.41 (2H, d, J=6.6 Hz), 1.87-1.55 (5H, m), 1.50-1.08 (4H, m), 1.47(9H, s), 1.04-0.81 (2H, m).

EXAMPLE 5 (3)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-((4R)-3-t-butoxycarbonyl-1-oxothiazolidin-4-ylcarbonylamino)propanamide

TLC: Rf 0.40 (chloroform:methanol=19:1);

NMR(CD₃OD): δ 7.23-7.20 (2H, m), 6.87-6.82 (2H, m), 5.13-4.83 (1H, m),4.70-4.20 (5H, m), 3.76 and 3.75 (3H, s), 3.60-3.30 (2H, m), 3.12-2.72(2H, m), 2.43-2.38 (2H, m), 1.85-1.60 (5H, m), 1.50-1.09 (4H, m), 1.45and 1.47 (9H, s), 1.00-0.83 (2H, m).

EXAMPLE 5 (4)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylsulfinyl-2-((4R)-3-t-butoxycarbonyl-1-oxothiazolidin-4-ylcarbonylamino)propanamide

TLC: Rf 0.40 (chloroform:methanol=14:1);

NMR(CD₃OD): δ 7.23-7.17 (2H, m), 6.88-6.81 (2H, m), 5.10-4.70 (1H, m),4.65-4.50 (2H, m), 4.41-4.10 (3H, m), 3.75 (3H, s), 3.67-2.85 (4H, m),2.85-2.57 (2H, m), 2.02-1.00 (11H, m), 1.48-1.45 (9H, m).

EXAMPLE 5 (5)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-((2RS,4R)-3-t-butoxycarbonyl-2-methoxymethylthiazolidin-4-ylcarbonylamino)propanamide

TLC: Rf 0.24 (ethyl acetate:hexane=2:3);

NMR(CD₃OD): δ 7.26-7.20 (m, 2H), 6.88-6.82 (m, 2H), 5.26 (t, J=5 Hz,1H), 4.57-4.44 (m, 2H), 4.38-4.23 (m, 2H), 3.84 (dd, J=10, 5 Hz, 1H),3.76 (s, 3H), 3.58 (dd, J=10, 3 Hz, 1H), 3.47 (s, 3H), 3.35-3.29 (m,2H), 2.97-2.63 (m, 2H), 2.41 (bd, J=6 Hz, 2H), 1.86-1.60 (m, 5H),1.51-1.07 (m, 13H), 0.99-0.83 (m, 2H).

EXAMPLE 5 (6)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-((2RS,4R)-3-t-butoxycarbonyl-2-hydroxymethylthiazolidin-4-ylcarbonylamino)propanamide

TLC: Rf 0.32 (ethyl acetate:methylene chloride=1:2);

NMR(CDCl₃): δ 7.75-7.53 (b, 1H), 7.25-7.15 (m, 3H), 6.83-6.80 (m, 2H),5.30-5.10 (m, 1H), 4.70-4.62 (m, 1H), 4.62-4.46 (m, 1H), 4.46-4.28 (m,2H), 4.20-3.98 (m, 1H), 3.79 (s, 3H), 3.67 (dd, J=11, 3 Hz, 1H), 3.39(dd, J=12, 6 Hz, 1H), 3.33 (dd, J=12, 8 Hz, 1H), 3.05-2.85 (b, 2H),2.49-2.32 (m, 2H), 1.83-1.57 (m, 6H), 1.50-1.30 (m, 10H), 1.30-1.03 (m,3H), 1.00-0.81 (m, 2H).

EXAMPLE 5 (7)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-((2RS,4R)-3-t-butoxycarbonyl-2-(2-methylthioethyl)thiazolidin-4-ylcarbonylamino)propanamide

TLC: Rf 0.57 (ethyl acetate:hexane=1:1);

NMR(CDCl₃): δ 7.35-7.13 (m, 4H), 6.8˜6.80 (m, 2H), 5.28 (dd, J=9, 6 Hz,1H), 4.64 (t, J=8 Hz, 1H), 4.61-4.51 (m, 1H), 4.42 (dd, J=15, 6 Hz, 1H),4.33 (dd, J=15, 6 Hz, 1H), 3.78 (s, 3H), 3.37-3.29 (m, 2H), 3.25-3.10(m, 1H), 2.80 (dd, J=14, 6Hz, 1H), 2.69-2.50 (m, 2H), 2.48-2.20 (m, 3H),2.12 (s, 3H), 2.03-1.87 (m, 1H), 1.82-1.55 (m, 5H), 1.51-1.33 (m, 10H),1.30-1.03 (m, 3H), 1.00-0.78 (m, 2H).

EXAMPLE 5 (8)(2R)-N-(1-benzylpiperidin-4-yl)-3-cyclohexylmethylthio-2-((4R)-3-t-butoxycarbonyl-1,1-dioxothiazolidin-4-ylcarbonylamino)propanamide

TLC: Rf 0.33 (chloroform:methanol=19:1);

NMR(CD₃OD): δ 7.35-7.20 (m, 5H), 5.07-4.86 (m, 1H), 4.74 (dd, J=11.8,1.6 Hz, 1H), 4.43 (t, J=7.0 Hz, 1H), 4.34 (d, J=11.8 Hz, 1H), 3.74-3.56(m, 2H), 3.55 (s, 2H), 3.50-3.35 (m, 1H), 2.95-2.70 (m, 4H), 2.45 (d,J=6.6 Hz, 2H), 2.26-2.08 (m, 2H), 1.92-0.83 (m, 15H), 1.48 (m, 9H).

EXAMPLE 5 (9)(2R)-N-(1-benzylpiperidin-4-yl)-3-cyclohexylmethylthio-2-((4R)-3-t-butoxycarbonyl-1-oxothiazolidin-4-ylcarbonylamino)propanamide

TLC: Rf 0.40 (chloroform:methanol=9:1);

NMR(CD₃OD): δ 7.35-7.20 (m, 5H), 5.16-4.90 (m, 1H), 4.70-4.18 (m, 3H),3.74-3.40 (m, 3H), 3.52 (s, 2H), 3.20-2.70 (m, 4H), 2.47-2.40 (m, 2H),2.23-2.04 (m, 2H), 1.93-0.80 (m, 15H), 1.50 (s, 9H).

EXAMPLE 5 (10)(2R)-N-(1-benzylpiperidin-4-yl)-3-cyclohexylmethylthio-((4S)-3-t-butoxycarbonyl-2-oxooxazolidin-4-ylcarbonylamino)propanamide

TLC: Rf 0.28 (methanol:chloroform=1:19);

NMR(CDCl₃): δ 7.32-7.25 (m, 5H), 7.19 (d, J=6.9 Hz, 1H), 6.46 (d, J=8.1Hz, 1H), 4.70 (dd, J=8.4, 5.4 Hz, 1H), 4.50-4.37 (m, 3H), 3.86-3.72 (m,1H), 3.51 (s, 2H), 2.95 (dd, J=14.1, 4.8 Hz, 1H), 2.82-2.78 (m, 2H),2.69 (dd, J=13.8, 8.1 Hz, 1H), 2.54 (dd, J=12.9, 6.9 Hz, 1H), 2.47 (dd,J=12.9, 6.9 Hz, 1H), 2.20-2.13 (m, 2H), 1.96-1.38 (m, 19H), 1.32-1.06(m, 3H), 1.02-0.84 (m, 2H).

EXAMPLE 6˜EXAMPLE 6 (2)

By the same procedures described in Reference Example 5→ReferenceExample 6, using compounds prepared in Example 5 (5)˜Example 5 (7), thefollowing compounds of the present invention were obtained.

EXAMPLE 6(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-((2RS,4R)-2-methoxymethylthiazolidin-4-ylcarbonylamino)propanamide

TLC: Rf 0.42 and 0.38 (methanol:methylene chloride=1:19);

NMR(CD₃OD): δ 7.25-7.18 (m, 2H), 6.89-6.83 (m, 2H), 4.77 and 4.72 (t,J=6 Hz, 1H), 4.54-4.45 (m, 1H), 4.34 (d, J=15 Hz, 1H), 4.30 (d, J=15 Hz,1H), 4.26-4.20 (m) and 4.02 (t, J=6 Hz)(1H), 3.76 (s, 3H), 3.64-3.45 (m,2H), 3.40 and 3.39 (s, 3H), 3.29-3.15 (m, 1H), 3.09-3.00 (m, 1H),2.98-2.77 (m, 2H), 2.43-2.37 (m, 2H), 1.86-1.60 (m, 5H), 1.50-1.34 (m,1H), 1.34-1.06 (m, 3H), 0.99-0.84 (m, 2H).

EXAMPLE 6 (1)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-((2RS,4R)-2-hydroxymethylthiazolidin-4-ylcarbonylamino)propanamide

TLC: Rf 0.39 (methanol:methylene chloride=1:19);

NMR(CD₃OD): δ 7.26-7.18 (m, 2H), 6.90-6.83 (m, 2H), 4.70 (t, J=5 Hz) and4.63 (t, J=6 Hz)(1H), 4.53-4.46 (m, 1H), 4.34 (d, J=15 Hz, 1H), 4.29 (d,J=15 Hz, 1H), 4.26-4.21 (m) and 4.03 (t, J=8 Hz)(1H), 3.76 (s, 3H),3.75-3.56 (m, 2H), 3.28-3.14 (m, 1H), 3.05 (dd, J=10, 7 Hz, 1H),2.97-2.88 (m, 1H), 2.86-2.76 (m, 1H), 2.39 and 2.41 (d, J=7 Hz, 2H),1.83-1.57 (m, 5H), 1.50-1.30 (m, 1H), 1.30-1.03 (m, 3H), 1.00-0.81 (m,2H).

EXAMPLE 6 (2)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-((2RS,4R)-2-(2-methylthioethyl)thiazolidin-4-ylcarbonylamino)propanamide

TLC: Rf 0.31 (methanol:methylene chloride=1:99);

NMR(CD₃OD): δ 7.25-7.18 (m, 2H), 6.90-6.83 (m, 2H), 4.65 (t, J=6 Hz,1H), 4.58-4.45 (m, 1H), 4.39-4.25 (m, 2H), 4.30-4.25 (m) and 3.92 (t,J=8 Hz)(1H), 3.77 (s, 3H), 3.41-2.78 (m, 4H), 2.71-2.58 (m, 2H), 2.39and 2.41 (d, J=7 Hz, 2H), 2.23-2.08 (m, 1H), 2.10 (s, 3H), 2.05-1.92 (m,1H), 1.86-1.58 (m, 5H), 1.50-1.34 (m, 1H), 1.34-1.06 (m, 3H), 1.00-0.84(m, 2H).

EXAMPLE 7(2R)-N-(4-phenoxybenzyl)-3-cyclohexylmethylthio-2-((4R)-3-hydroxymethylcarbonylthiazolidin-4-ylcarbonylamino)propanamide

A compound prepared in Example 1 (5) (185 mg) was dissolved intomethanol (10 ml). Thereto, an aqueous solution of 1N—NaOH (0.4 ml) wasadded. The mixture was stirred for 2.5 hours at room temperature. Thereaction mixture was centurifized by addition of 1N HCl andconcentrated. To the residue, water was added. The mixture was extractedwith methylene chloride. The extract was washed by saturated solution ofsodium chloride, dried over anhydrous sodium sulfate and concentrated toobtain the compound (172 mg) of the present invention having thefollowing physical data.

TLC: Rf 0.41 (chloroform:methanol=19:1);

NMR(CD₃OD): δ 7.37-7.29 (m, 4H), 7.13-7.04 (m, 1H), 7.00-6.89 (m, 4H),4.95-4.14 (m, 8H), 3.43-3.30 (m, 1H), 3.23-3.08 (m, 1H), 2.97 (dd,J=13.8, 6.3 Hz, 1H), 2.79 (dd, J=13.8, 7.8 Hz, 1H), 2.44-2.40 (m, 2H),1.90-0.80 (m, 11H).

EXAMPLE 7 (1)˜EXAMPLE 7 (2)

By the same procedure described in Example 7, using compounds preparedin Example 1 (2) and Example 1 (4), the following compounds of thepresent invention were obtained.

EXAMPLE 7 (1)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-((4R)-3-hydroxymethylcarbonylthiazolidin-4-ylcarbonylamino)propanamide

TLC: Rf 0.51 (chloroform:methanol=9:1);

NMR(CD₃OD): δ 7.24-7.21 (2H, m), 6.86-6.83 (2H, m), 4.86-4.45 (4H, m),4.40-4.10 (4H, m), 3.76 (3H, s), 3.45-2.92 (3H, m), 2.81-2.71 (1H, m),2.42-2.39 (2H, m), 1.85-1.60 (5H, m), 1.50-1.08 (4H, m), 0.99-0.84 (2H,m).

EXAMPLE 7 (2)(2R)-N-(1-benzylpiperidin-4-yl)-3-cyclohexylmethylthio-2-((4R)-3-hydroxymethylcarbonylthiazolidin-4-ylcarbonylamino)propanamide

TLC: Rf 0.48 (chloroform:methanol=9:1);

NMR(CD₃OD): δ 7.35-7.20 (m, 5H), 4.90-4.00 (m, 6H), 3.75-3.53 (m, 1H),3.53 (s, 2H), 3.45-2.66 (m, 6H), 2.43 (d, 2H, J=6.8 Hz), 2.20-2.05 (m,2H), 1.90-0.80 (m, 15H).

EXAMPLE 8˜EXAMPLE 8 (1)

By the same procedure described in Example 2, using compounds preparedin Example 3 and 3 (7), the following compounds of the present inventionwere obtained.

EXAMPLE 8(2R)-N-(4-phenoxybenzyl)-3-cyclohexylmethylthio-2-((4R)-3-(morpholin-4-ylcarbonylmethyl)thiazolidin-4-ylcarbonylamino)propanamide

TLC: Rf 0.41 (chloroform:methanol=19:1);

NMR(CD₃OD): δ 7.38-7.23 (m, 4H), 7.12-7.04 (m, 1H), 6.99-6.87 (m, 4H),4.55 (dd, J=7.6, 5.3 Hz, 1H), 4.43 (d, J=15.0 Hz, 1H), 4.35 (d, J=15.0Hz, 1H), 4.25 (d, J=10.5 Hz, 1H), 4.06 (d, J=10.5 Hz, 1H), 4.05-4.00 (m,1H), 3.72-3.42 (m, 10H), 3.39-3.31 (m, 1H), 3.20 (dd, J=11.0, 8.0 Hz,1H), 3.00 (dd, J=13.8, 5.3 Hz, 1H), 2.90 (dd, J=13.8, 7.6 Hz, 1H), 2.40(d, J=6.6 Hz, 2H), 1.90-0.80 (m, 11H).

EXAMPLE 8 (1)(2R)-N-(1-benzylpiperidin-4-yl)-3-cyctohexylmethylthio-2-((4R)-3-(morpholin-4-ylcarbonylmethyl)thiazolidin-4-ylcarbonylamino)propanamide

TLC: Rf 0.48 (chloroform:methanol=9:1);

NMR(CD₃OD): δ 7.35-7.20 (m, 5H), 4.46 (dd, J=7.5, 5.0 Hz, 1H), 4.25 (d,J=10.0 Hz, 1H), 4.07 (d, J=10.0 Hz, 1H), 4.06-4.00 (m, 1H), 3.76-3.48(m, 11H), 3.51 (s, 2H), 3.37 (dd, J=11.0, 3.4 Hz, 1H), 3.18 (dd, J=11.0,8.0 Hz, 1H), 2.99-2.77 (m, 4H), 2.42 (d, J=7.0 Hz, 2H), 2.20-2.04 (m,2H), 1.90-0.80 (m, 15H).

EXAMPLE 9(2R)-N-(4-phenoxybenzyl)-3-cyclohexylmethylthio-2-((4R)-3-(2-(tetrahydropyran-2-yloxy)ethyl)thiazolidin-4-ylcarbonylamino)propanamide

A compound prepared in Example 3 (8) (165 mg) and dihydropyran (68 mg)were dissolved into anhydrous tetrahydrofuran (6 ml). Thereto, p-toluenesulfonic acid (63 mg) and pyridium p-toluene sulfonate (amount ofcatalyst) were added. The mixture was stirred for 3.5 hours at roomtemperature. To the reaction mixture, triethylamine (a few drops) wasadded. The mixture was concentrated. The residue was purified withcolumn chromatography on silica gel (chloroform:methanol=50:1) to obtainthe compound (70 mg) of the present invention having the followingphysical data.

TLC: Rf 0.39 (chloroform:methanol=19:1);

NMR(CD₃OD): δ 7.38-7.25 (m, 4H), 7.147.05 (m, 1H), 6.98-6.90 (m, 4H),5.16-5.09 (m, 1H), 4.52-4.45 (m, 1H), 4.37 (s, 2H), 4.26-4.08 (m, 3H),4.00-3.50 (m, 4H), 3.46-3.35 (m, 1H), 3.14-2.70 (m, 5H), 2.40 (d, J=7.0Hz, 2H), 2.00-0.80 (m, 17H).

EXAMPLE 10(2R)-N-(4-phenoxybenzyl)-3-cyclohexylmethylthio-2-((4R)-3-(2-methoxyethyl)thiazolidin-4-ylcarbonylamino)propanamide.hydrochloride

A compound prepared in Example 3 (10) (45 mg) was dissolved into ethylacetate (2 ml). Thereto, a solution of 4N HCl-ethyl acetate (0.05 ml)was added. The mixture was stirred at room temperature. The solvent wasdistilled off. The reside was washed by a mixture solvent of ethylacetate and hexane to obtain the compound (30 mg) having the followingphysical data.

TLC: Rf 0.53 (chloroform:methanol=19:1);

NMR(CD₃OD): δ 7.38-7.25 (m, 4H), 7.14-7.05 (m, 1H), 6.97-6.88 (m, 4H),4.70 (d, J=10.2 Hz, 1H), 4.57-4.49 (m, 2H), 4.39-4.34 (m, 3H), 3.72-3.25(m, 6H), 3.35 (s, 3H), 2.95 (dd, J=13.5, 6.3 Hz, 1H), 2.80 (dd, J=13.5,8.0 Hz, 1H), 2.45 (d, J=6.6 Hz, 2H), 1.90-0.80 (m, 11H).

EXAMPLE 10 (1)˜EXAMPLE 10 (2)

By the same procedure described in Example 10 using compounds preparedin Example 3 (1) and Example 8, the following compounds of the presentinvention were obtained.

EXAMPLE 10 (1)(2R)-N-(4-nitrobenzyl)-3-cyclohexylmethylthio-2-((4R)-3-(3-methylbutyl)thiazolidin-4-ylcarbonylamino)propanamide.hydrochloride

TLC: Rf 0.60 (ethyl acetate:hexane=1:1);

NMR(CD₃OD): δ 8.24-8.15 (2H, m), 7.597.51 (2H, m), 4.74 (1H, d, J=10.2Hz), 4.62 (1H, dd, J=8.8, 5.8 Hz), 4.51 (2H, s), 4.47-4.43 (1H, m) 4.37(1H, d, J=10.2 Hz), 3.67 (1H, dd, J=12.0, 8.0 Hz), 3.49-3.22 (3H, m),3.00 (1H, dd, J=13.6, 5.6 Hz), 2.81 (1H, dd, J=13.6, 8.8 Hz), 2.48 (2H,d, J=7.0 Hz), 1.90-0.84 (20H, m).

EXAMPLE 10 (2)(2R)-N-(4-phenoxybenzyl)-3-cyclohexylmethylthio-2-((4R)-3-(morpholin-4-ylcarbonylmethyl)thiazolidin-4-ylcarbonylamino)propanamide.hydrochloride

TLC: Rf 0.37 (methylene chloride:methanol=19:1);

NMR(CD₃OD): δ 7.36-7.28 (m, 4H), 7.12-7.06 (m, 1H), 6.97-6.89 (m, 4H),4.60-4.52 (m, 2H), 4.43-4.31 (m, 4H), 4.20 (d, J=16.5 Hz, 1H), 4.16 (d,J=16.5 Hz, 1H), 3.73-3.32 (m, 10H), 2.96 (dd, J=13.8, 6.3 Hz, 1H), 2.89(dd, J=13.8, 7.8 Hz, 1H), 2.43 (d, J=6.6 Hz, 2H), 1.83-1.59 (m, 5H),1.50-1.36 (m, 1H), 1.30-1.08 (m, 3H), 0.98-0.86 (m, 2H).

EXAMPLE 11˜EXAMPLE 11 (4)

By the same procedures described in Example 1→Example 10, using(2R)-N-(1-benzylpiperidin-4-yl)-3-cyclohexylmethylthio-2-((4R)-thiazolidin-4-ylcarbonylamino)propanamideprepared by the same procedures described in Reference Example1→Reference Example 2→Reference Example 3→Reference Example 4→ReferenceExample 5→Reference Example 6, the following compounds of the presentinvention were obtained.

EXAMPLE 11(2R)-N-(1-benzylpiperidin-4-yl)-3-cyclohexylmethylthio-2-((4R)-3-(2-methoxyethoxycarbonyl)thiazolidin-4-ylcarbonylamino)propanamide.hydrochloride

TLC: Rf 0.58 (methanol:chloroform=1:9);

NMR(CD₃OD): δ 7.38-7.24 (m, 5H), 4.71-4.42 (m, 4H), 4.27 (br, s, 2H),3.74-3.52 (m, 5H), 3.38 (dd, J=12.3, 7.5 Hz, 1H), 3.36 (s, 3H), 3.17(dd, J=12.3, 4.8 Hz, 1H), 2.96-2.92 (m, 3H), 2.77 (dd, J=13.5, 8.1 Hz,1H), 2.44 (d, J=6.9 Hz, 2H), 2.30-2.23 (m, 2H), 1.92-1.78 (m, 4H),1.76-1.36 (m, 6H), 1.34-1.08 (m, 3H), 1.02-0.86 (m, 2H).

EXAMPLE 11 (1)(2R)-N-(1-benzylpiperidin-4-yl)-3-cyclohexylmethylthio-2-((4R)-3-chloromethoxycarbonylthiazolidin-4-ylcarbonylamino)propanamide.hydrochloride

TLC: Rf 0.53 (methanol:chloroform=1:9);

NMR(CD₃OD): δ 7.41-7.23 (m, 5H), 5.89-5.79 (m, 2H), 4.71-4.66 (m, 2H),4.59-4.51 (m, 1H), 4.44 (t, J=6.6HZ, 1H), 3.77-3.52 (m, 3H), 3.443.37(m, 1H), 3.17 (dd, J=12.0, 4.5 Hz, 1H), 3.01-2.68 (m, 4H), 2.44 (d,J=6.3 Hz, 2H), 2.36-2.12 (m, 2H), 1.94-1.08 (m, 12H), 1.01-0.85 (m, 3H).

EXAMPLE 11 (2)(2R)-N-(1-benzylpiperidin-4-yl)-3-cyclohexylmethylthio-2-((4R)-3-(3,3-dimethylbutyryl)thiazolidin-4-ylcarbonylamino)propanamide.hydrochloride

TLC: Rf 0.52 (chloroform:methanol=9:1);

NMR(DMSO-d₆, 100° C.): δ 11.01-10.73 (br, 1H), 8.03-7.73 (br, 2H),7.62-7.60 (m, 2H), 7.44-7.43 (m, 3H), 4.88 (dd, J=7.5, 4.0 Hz, 1H), 4.83(d, J=9.5 Hz, 1H), 4.57-4.35 (br, 2H), 4.32-4.15 (br, 2H), 4.02-3.71(br, 1H), 3.36-3.24 (br, 3H), 3.14-2.92 (m, 3H), 2.87-2.79 (br, 2H),2.43 (d, J=7.0 Hz, 2H), 2.33-1.86 (br, 6H), 1.77-1.59 (m, 5H), 1.47-1.38(m, 1H), 1.26-0.89 (m, 14H).

EXAMPLE 11 (3)(2R)-N-(1-benzylpiperidin-4-yl)-3-cyclohexylmethylthio-2-((4R)-3-cyclopentylcarbonylthiazolidin-4-ylcarbonylamino)propanamide.hydrochloride

TLC: Rf 0.57 (chloroform:methanol=9:1);

NMR(CD₃OD): δ 7.53-7.47 (m, 5H), 4.90˜4.65 (m, 2H), 4.60-4.37 (m, 2H),4.31 (s, 2H), 4.06-3.83 (m, 1H), 3.60-3.00 (m, 5H), 3.00-2.80 (m, 2H),2.44 (d, J=7.0 Hz, 2H), 2.20-2.00 (m, 2H), 2.00-1.50 (m, 16H), 1.50-1.40(m, 1H), 1.38-1.12 (m, 4H), 1.00-0.90 (m, 2H).

EXAMPLE 11 (4)(2R)-N-(1-benzylpiperidin-4-yl)-3-cyclohexylmethylthio-2-((4R)-3-benzoylthiazolidin-4-ylcarbonylamino)propanamide.hydrochloride

TLC: Rf 0.57 (chloroform:methanol=9:1);

NMR(CD₃OD): δ 7.70-7.30 (m, 10H), 5.00-4.60 (m, 3H), 4.40 (t, J=6.8 Hz,1H), 4.35-4.15 (m, 2H), 4.14-3.85 (m, 1H), 3.60-2.70 (m, 8H), 2.44 (d,J=7.0 Hz, 2H), 2.20-1.90 (m, 2H), 1.90-1.73 (m, 3H), 1.73-1.60 (m, 3H),1.50-1.40 (m, 1H), 1.37-1.10 (m, 4H), 1.00-0.88 (m, 2H).

EXAMPLE 12(2R)-N-(1-benzylpiperidin-4-yl)-3-cyclohexylmethylthio-((4R)-3-(3,3-dimethyl-1,2-dioxobutyl)thiazolidin-4-ylcarbonylamino)propanamide.hydrochloride

A solution of a compound prepared in Example 1 (13) (400 mg) intetrahydrofuran (5 ml) was cooled to −78° C. Thereto, t-butyl magnesiumchloride (1.0 ml, 2.0M in tetrahydrofuran) was added. The mixture wasstirred for 2 hours at −78° C., and then for 30 minutes at roomtemperature. The reaction mixture was quenched by saturated solution ofammonium chloride and extracted with ethyl acetate. The extract waswashed by saturated solution of sodium chloride, dried over anhydroussodium sulfate and concentrated. The residue was purified with columnchromatography on silica gel (ethyl acetate:hexane=2:1→3:1). Thepurified product was dissolved into ethyl acetate. Thereto, a solutionof 4N HCl-ethyl acetate was added. The mixture was concentrated. Theresidue was washed by diethyl ether to obtain the compound (184.9 mg) ofthe present invention having the following physical data.

TLC: Rf 0.24 (ethyl acetate:hexane=3:1);

NMR(CD₃OD): δ 7.58-7.43 (m, 5H), 4.92-4.76 (m, 1H), 4.60-4.51 (m, 2H),4.44-4.35 (m, 1H), 4.31 (s, 2H), 4.02-3.84 (m, 1H), 3.60-3.00 (m, 6H),2.96-2.70 (m, 2H), 2.48-2.41 (m, 2H), 2.22-2.02 (m, 2H), 1.90-1.61 (m,7H), 1.55-1.35 (m, 1H), 1.35-1.01 (m, 12H), 1.04-0.87 (m, 2H).

EXAMPLE 13˜EXAMPLE 13 (2)

By the same procedures described in Example 5→Example 10, the followingcompounds of the present invention were obtained.

EXAMPLE 13(2R)-N-(1-benzylpiperidin-4-yl)-3-cyclohexylmethylthio-((4R)-2,2,5,5-tetramethylthiazolidin-4-ylcarbonylamino)propanamide.2hydrochloride

TLC: Rf 0.38 (methylene chloride:methanol=93:7);

NMR(CD₃OD): δ 7.60-7.45 (m, 5H), 4.66-4.49 (m, 2H), 4.41 and 4.31 (s,2H), 4.12-4.05 and 3.97-3.85 (m, 1H), 3.56-3.46 and 3.42-3.23 (m, 2H),3.42-3.23 and 3.17-3.05 (m, 2H), 3.02-2.79 (m, 2H), 2.53 and 2.48 (d,J=7 Hz, 2H), 2.18-2.02 (m, 2H), 1.95-1.60 (m, 16H), 1.53-1.37 (m, 4H),1.35-1.09 (m, 3H), 1.05-0.88 (m, 2H).

EXAMPLE 13 (1)(2R)-N-(1-benzylpiperidin-4-yl)-3-cyclohexylmethylthio-((2S)-1-t-butoxycarbonyl-4-oxopyrrolidin-2-ylcarbonylamino)propanamide.hydrochloride

TLC: Rf 0.34 (methanol:chloroform=1:19);

NMR(CD₃OD): δ 7.55-7.45 (m, 5H), 4.72 (dd, J=9.9, 6.0 Hz, 1H), 4.39-4.28(m, 3H), 4.02-3.74 (m, 3H), 3.582.66 (m, 7H), 2.55-2.38 (m, 3H),2.18-0.86 (m, 24H).

EXAMPLE 13 (2)(2R)-N-(1-benzylpiperidin-4-yl)-3-cyclohexylmethylthio-((2S,4R)-1-t-butoxycarbonyl-4-hydroxypyrrolidin-2-ylcarbonylamino)propanamide.hydrochloride

TLC: Rf 0.34 (methanol:chloroform=1:9);

NMR(CD₃OD): δ 7.56-7.46 (m, 5H), 4.43-4.25 (m, 5H), 3.99-3.84 (m, 1H),3.62-3.44 (m, 4H), 3.24-3.04 (m, 2H), 2.91-2.70 (m, 2H), 2.47-2.41 (m,2H), 2.28-1.08 (m, 22H), 1.04-0.86 (m, 2H).

EXAMPLE 14˜EXAMPLE 4 (2)

By the same procedures described in Reference Example 4 Example 10 using(2R)-N-(1-benzylpiperidin-4-yl)-2-amino-3-cyclohexylmethylthiopropanamide.2hydrochlorideprepared by the same procedures described in Reference Example1→Reference Example 2→Reference Example 3, the following compounds ofthe present invention were obtained.

EXAMPLE 14(2R)-N-(1-benzylpiperidin-4-yl)-3-cyclohexylmethylthio-2-((4R)-3-isopropylsulfonylthiazolidin-4-ylcarbonylamino)propanamide.hydrochloride

TLC: Rf 0.51 (methanol:chloroform=1:9);

NMR (DMSO-d₆) δ 10.64-10.46 (br, 1H), 8.33-8.22 (m, 2H), 7.61-7.53 (br,1H), 2H), 7.45-7.43 (m, 3H), 4.88-4.75 (m, 2H), 4.42-4.21 (m, 4H),3.98-3.75 (br, 1H), 3.50-2.92 (m, 7H), 2.78-2.60 (m, 2H), 2.39 (d, J=6.6Hz, 2H), 2.05-1.53 (m, 9H), 1.47-1.01 (m, 10H), 0.99-0.81 (m, 2H).

EXAMPLE 4 (1)(2R)-N-(1-benzylpiperidin-4-yl)-3-cyclohexylmethylthio-2-((4R)-3-cyclopentylsulfonylthiazolidin-4-ylcarbonylamino)propanamide.hydrochloride

TLC: Rf 0.46 (methanol:chloroform=1:9);

NMR (DMSO-d₆): δ 10.57-10.41 (br, 1H), 8.35-8.14 (m, 2H), 7.61-7.53 (br,2H), 7.45-7.43 (m, 3H), 4.89-4.76 (m, 2H), 4.44-4.21 (m, 4H), 3.97-3.68(m, 2H), 3.39-2.92 (m, 6H), 2.78-2.61 (m, 2H), 2.39 (d, J=6.9 Hz, 2H),1.97-1.53 (m, 17H), 1.41-1.00 (m, 4H), 0.92-0.81 (m, 2H).

EXAMPLE 14 (2)(2R)-N-(1-benzylpiperidin-4-yl)-3-cyclohexylmethylthio-2-((4R)-3-isobutylsulfonylthiazolidin-4-ylcarbonylamino)propanamide.hydrochloride

TLC: Rf 0.56 (methanol:chloroform=1:9);

NMR (DMSO-d₆): δ 10.45-10.31 (br, 1H), 8.30-8.08 (m, 2H), 7.57-7.44 (m,5H), 4.83-4.72 (m, 2H), 4.44-4.20 (m, 4H), 3.98-3.65 (m, 1H), 3.41-2.94(m, 8H), 2.86-2.64 (m, 2H), 2.38 (d, J=6.9 Hz, 2H), 2.20-2.08 (m, 1H),2.00-1.56 (m, 9H), 1.41-1.28 (m, 1H), 1.23-1.00 (m, 9H), 0.91-0.80 (m,2H).

EXAMPLE 15(2R)-N-(1-benzylpiperidin-4-yl)-3-cyclohexylmethylthio-2-((4R)-3-allyloxycarbonylthiazolidin-4-ylcarbonylamino)propanamide.hydrochloride

By the same procedures described in Example 10 using a compound preparedin Example 1 (10), the compound having the following physical data.

TLC: Rf 0.39 (methanol:methylene chloride=1:19);

NMR (CD₃OD) δ 7.58-7.45 (m, 5H), 6.07-5.87 (m, 1H), 5.41-5.14 (m, 2H),4.74-4.39 (m, 6H), 4.31 (s, 2H), 4.10-3.84 (m, 1H), 3.55-3.33 (m, 3H),3.22-3.05 (m, 3H), 3.02-2.70 (m, 2H), 2.50-2.40 (m, 2H), 2.20-2.00 (m,2H), 1.90-1.60 (m, 7H), 1.53-1.35 (m, 1H), 1.35-1.08 (m, 3H), 1.05-0.85(m, 2H).

FORMULATION EXAMPLE Formulation Example 1

The following compounds were admixed in conventional method and punchedout to obtain 100 tablets each containing 50 mg of active ingredient.

(2R)-N-(1-benzylpiperidin-4-yl)-3-cyclohexylmethylthio-2-((4R)- 5.0 g3-(3,3-dimethylbutyryl)thiazolidin-4-ylcarbonylamino)propanamideCarboxymethylcellulose calcium (disintegrating agent) 0.2 g Magnesiumstearate (lubricating agent) 0.1 g Micro crystalline cellulose 4.7 g

Formulation Example 2

The following components were admixed in a conventional method, and thesolution was sterilized in a conventional method, placed 5 ml portionsinto ampoules and freeze-dried in a conventional method to obtain 100ampoules each containing 20 mg of active ingredient.

-   -   (2R)-N-(1-benzylpiperidin-4-yl)-3-cyclohexylmethylthio-2-((4R)-3-(3,3-dimethylbutyryl)thiazolidin-4-ylcarbonylamino)propanamide        . . . 2.00 g    -   mannitol . . . 20 g    -   distilled water . . . 500 ml

1. An amino acid compound of the formula (I)

wherein, R¹ is thiazolidinyl, oxazolidinyl or pyrrolidinyl which issubstituted with (a) four C1-4 alkyl or (b) one substituent selectedfrom the following (i)-(xii), and which may be substituted with 1 to 3of substituent(s) selected from the group consisting of (i)-(xxiii): (i)oxo, (ii) C5-8 alkyl, (iii) —COO—R⁵ (in which, R⁵ is hydrogen, C5-8alkyl, C2-8 alkenyl, or C1-4 alkyl substituted with 1 to 3 of halogen orC1-4 alkoxy), (iv) —(C1-4 alkylene)-COOR⁶ (in which, R⁶ is hydrogen,C1-8 alkyl, C2-8 alkenyl or C1-4 alkyl substituted with 1 to 3 ofhalogen), (v) —CO—R⁷ (in which, R⁷ is C5-8 alkyl, C2-4 alkenyl,carbocyclic ring, heterocyclic ring or C1-8 alkyl substituted with onesubstituent selected from the following (1)-(8): (1) carbocyclic ring,(2) heterocyclic ring, (3) hydroxy, (4) C1-4 alkoxy, (5) —OCO—(C1-4alkyl), (6) —O—(C1-4 alkylene)-O—(C1-4 alkyl), (7) NR⁸R⁹ (in which, R⁸and R⁹ each, independently, is hydrogen or C1-4 alkyl), (8) halogen),(vi) —(C1-4 alkylene)-CO—R¹⁰ (in which, R¹⁰ is C1-8 alkyl, C2-4 alkenyl,carbocyclic ring, heterocyclic ring or C1-8 alkyl substituted with onesubstituent selected from the following (1)-(8): (1) carbocyclic ring,(2) heterocyclic ring, (3) hydroxy, (4) C1-4 alkoxy, (5) —OCO—(C1-4alkyl), (6) —O—(C1-4 alkylene)-O—(C1-4 alkyl), (7) NR¹¹R¹² (in which,R¹¹ and R¹² each, independently, is hydrogen or C1-4 alkyl), (8)halogen), (vii) —CO—CO—R¹³, (viii) —CO—(C1-4 alkylene)-CO—R¹⁴, (ix)—SO₂—R¹⁵ (in which, R¹³, R¹⁴ and R¹⁵ each, independently, is C1-8 alkyl,C2-4 alkenyl, carbocyclic ring, heterocyclic ring, hydroxy, C1-4 alkoxyor C1-8 alkyl substituted with one substituent selected from thefollowing (1)-(8): (1) carbocyclic ring, (2) heterocyclic ring, (3)hydroxy, (4) C1-4 alkoxy, (5) —OCO—(C1-4 alkyl), (6) —O—(C1-4alkylene)-O—(C1-4 alkyl), (7) NR¹⁶R¹⁷ (in which, R¹⁶ and R¹⁷ each,independently, is hydrogen or C1-4 alkyl), (8) halogen), (x) —CONR¹⁸R¹⁹(in which, R¹⁸ is hydrogen or C1-4 alkyl which may be substituted withone phenyl, R¹⁹ is C1-8 alkyl or C2-4 alkenyl), (xi) C1-8 alkylsubstituted with 1 to 2 of substituent(s) selected from the groupconsisting of the following (1)-(7): (1) hydroxy, (2) C1-4 alkoxy, (3)—O—(C1-4 alkylene)-O—(C1-4 alkyl), (4) tetrahydropyran-2-yloxy, (5)—SR²⁰ (in which, R²⁰ is hydrogen or C1-4 alkyl), (6) halogen, (7)NR²¹R²² (in which, R²¹ and R²² each, independently, is hydrogen or C1-4alkyl), (xii) hydroxy, (xiii) C1-4 alkyl, (xiv) C1-4 alkoxy, (xv)phenyl, (xvi) phenoxy, (xvii) benzyloxy, (xviii) —SR²³ (in which, R²³ ishydrogen or C1-4 alkyl), (xix) C2-5 acyl, (xx) halogen, (xxi) C1-4alkoxycarbonyl, (xxii) nitro, (xxiii) —NR²⁴R²⁵ (in which, R²⁴ and R²⁵each, independently, is hydrogen, C1-4 alkyl or C1-4 alkoxycarbonyl, orR²⁴ and R²⁵ taken together with nitrogen atom to which is attachedrepresents 5 to 7-membered saturated heterocyclic ring necessarycontaining one nitrogen atom and optionally further containing onenitrogen atom or one oxygen atom), A is single bond, —CO— or —SO₂—, R²is hydrogen or C1-4 alkyl which may be substituted with one phenyl, D isC1-4 alkylene or C2-4 alkenylene, E is 1) —COO—, 2) —OCO—, 3) —CONR²⁶—(in which, R²⁶ is hydrogen or C1-4 alkyl), 4) —NR²⁷CO— (in which, R²⁷ ishydrogen or C1-4 alkyl), 5) —O—, 6) —S—, 7) —SO—, 8) —SO₂—, 9) —NR²⁸—(in which, R²⁸ is hydrogen or C1-4 alkyl), 10) —CO—, 11) —SO₂NR²⁹— (inwhich, R²⁹ is hydrogen or C1-4 alkyl) or 12) —NR³⁰SO₂— (in which, R³⁰ ishydrogen or C1-4 alkyl), R³ is cyclopentylmethyl or cyclohexylmethylwhich may be substituted with 1 to 3 of substituent(s) selected from thegroup consisting of the following (i)-(xi): (i) C1-4 alkyl, (ii) C1-4alkoxy, (iii) phenyl, (iv) phenoxy, (v) benzyloxy, (vi) —SR³¹ (in which,R³¹ is hydrogen or C1-4 alkyl), (vii) C2-5 acyl, (viii) halogen, (ix)C1-4 alkoxycarbonyl, (x) nitro, (xi) —NR³²R³³ (in which, R³² and R³³each, independently, is hydrogen, C1-4 alkyl or C1-4 alkoxycarbonyl, orR³² and R³³ taken together with nitrogen atom to which is attachedrepresents 5 to 7-membered saturated heterocyclic ring necessarycontaining one nitrogen atom and optionally further containing onenitrogen atom or one oxygen atom), J is 1) —O—, 2) —NR³⁴— (in which, R³⁴is hydrogen, C1-4 alkyl which may be substituted with one phenyl,NR³⁵R³⁶ (in which, R³⁵ and R³⁶ each, independently, is hydrogen or C1-4alkyl), hydroxy, C1-4 alkoxy, C1-4 alkylene)-OH, —(C1-4alkylene)-O—(C1-4 alkyl) or —(C1-4 alkylene)-O—(C2-5 acyl)), 3)—NR³⁷—NR³⁸— (in which, R³⁷ and R³⁸ each, independently, is hydrogen orC1-4 alkyl which may be substituted with one phenyl), 4) —NR³⁹—(C1-4alkylene)-NR⁴⁰— (in which, R³⁹ and R⁴⁰ each, independently, is hydrogenor C1-4 alkyl which may be substituted with one phenyl), 5) —NR⁴¹—(C1-4alkylene)-O— (in which, R⁴¹ is hydrogen or C1-4 alkyl which may besubstituted with one phenyl) or 6) —NR⁴²—(C1-4 alkylene)-S— (in which,R⁴² is hydrogen or C1-4 alkyl which may be substituted with one phenyl),R⁴ is R⁴⁻¹ or R⁴⁻², R⁴⁻¹ is piperidinyl which may be substituted with 1to 3 of substituent(s) selected from the group consisting of thefollowing (i)-(x): (i) C1-4 alkyl, (ii) C1-4 alkoxy, (iii) —SR⁴⁶ (inwhich, R⁴⁶ is hydrogen or C1-4 alkyl), (iv) C2-5 acyl, (v) halogen, (vi)C1-4 alkoxycarbonyl, (vii) nitro, (viii) —NR⁴⁷R⁴⁸ (in which, R⁴⁷ and R⁴⁸each, independently, is hydrogen, C1-4 alkyl or C1-4 alkoxycarbonyl),(ix) hydroxy, (x) —(C1-4 alkylene)-O—(C1-4 alkyl), R⁴⁻² is —L—M, —L— isa piperidine ring, M is 1) carbocyclic ring, 2) heterocyclic ring, 3)C1-4 alkyl substituted with 1 to 2 of substituent(s) selected from thegroup consisting of the following (i)-(ii): (i) carbocyclic ring, (ii)heterocyclic ring, 4) —O-(carbocyclic ring or heterocyclic ring), 5)—S-(carbocyclic ring or heterocyclic ring), 6) —NR⁴⁹-(carbocyclic ringor heterocyclic ring) (in which, R⁴⁹ is hydrogen or C1-4 alkyl which maybe substituted with one phenyl), 7) —O—(C1-4 alkylene)-(carbocyclic ringor heterocyclic ring), 8) —S—(C1-4 alkylene)-(carbocyclic ring orheterocyclic ring), 9) —NR⁵⁰—(C1-4 alkylene)-(carbocyclic ring orheterocyclic ring) (in which, R⁵⁰ is hydrogen, C1-4 alkyl which may besubstituted with one phenyl or C2-5 acyl which may be substituted with 1to 3 of halogen) or 10) —CO-(carbocyclic ring or heterocyclic ring), orthe said piperidine ring in L, and the said carbocyclic ring andheterocyclic ring in M may be substituted with 1 to 3 of substituent(s)selected from the group consisting of the following (i)-(xiv): (i) C1-4alkyl, (ii) C2-4 alkenyl, (iii) hydroxy, (iv) C1-4 alkoxy, (v) —(C1-4alkylene)-OH, (vi) —(C1-4 alkylene)-O—(C1-4 alkyl), (vii) halogen,(viii) NR⁵¹R⁵² (in which, R⁵¹ and R⁵² each, independently, is hydrogen,C1-4 alkyl or C1-4 alkoxycarbonyl, or R⁵¹ and R⁵² taken together withnitrogen atom to which is attached represents 5 to 7-membered saturatedheterocyclic ring necessary containing one nitrogen atom and optionallyfurther containing one nitrogen atom or one oxygen atom), (ix) SR⁵³ (inwhich, R⁵³ is hydrogen or C1-4 alkyl), (x) nitro, (xi) trifluoromethyl,(xii) C1-4 alkoxycarbonyl, (xiii) oxo, (xiv) C2-5 acyl or a non-toxicsalt thereof, or a hydrate thereof.
 2. A compound according to claim 1,in which E is —COO—, —O—, —S—, —SO— or —SO₂—.
 3. A compound according toclaim 1, in which E is —O— or —S—.
 4. A compound according to claim 1which is: 1)(2R)-N-(1-benzylpiperidin-4-yl)-3-cyclohexylmethylthio-2-((4R)-3-(pyridin-3-ylcarbonyl)thiazolidin-4-ylcarbonylamino)propanamide,2)(2R)-N-(1-benzylpiperidin-4-yl)-3-cyclohexylmethylthio-2-((4R)-3-acetyloxymethylcarbonylthiazolidin-4-ylcarbonylamino)propanamide,3)(2R)-N-(1-benzylpiperidin-4-yl)-3-cyclohexylmethylthio-2-((4R)-3-(2-methoxyacetyl)thiazolidin4ylcarbonylamino)propanamide,4)(2R)-N-(1-benzylpiperidin-4-yl)-3-cyclohexylmethylthio-2-((4R)-3-allyloxycarbonylthiazolidin-4-ylcarbonylamino)propanamide,5)(2R)-N-(1-benzylpiperidin-4-yl)-3-cyclohexylmethylthio-((4R)-3-(2-ethoxy-1,2-dioxoethyl)thiazolidin-4-ylcarbonylamino)propanamide,6)(2R)N-(1-benzylpiperidin-4-yl)-3-cyclohexylmethylthio-((4R)-3-phenylsulfonylthiazolidin-4-ylcarbonylamino)propanamide,7)(2R)N-(1-benzylpiperidin-4-yl)-3-cyclohexylmethylthio-2-((4R)-3-dimethylaminomethylcarbonylthiazolidin-4-ylcarbonylamino)propanamide,8)(2R)-N-(1-benzylpiperidin-4-yl)-3-cyclohexylmethylthio-2-((4R)-3-(morpholin-4-ylmethylcarbonyl)thiazolidin-4-ylcarbonylamino)propanamide,9)(2R)-N-(1-benzylpiperidin-4-yl)-3-cyclohexylmethylthio-2-((4R)-3-(3-hydroxy-3-methylbutyryl)thiazolidin-4-ylcarbonylamino)propanamide,10)(2R)-N-(1-benzylpiperidin-4-yl)-3-cyclohexyhmethylthio-2-((4R)-3-(2-hydroxyethyl)thiazolidin-4-ylcarbonylamino)propanamide,11)(2R)-N-(1-benzylpiperidin-4-yl)-3-cyclohexylmethylthio-2-((4R)-3-(3-hydroxy-3-methylbutyl)thiazolidin-4-ylcarbonylamino)propanamide,12)(2R)-N-(1-benzylpiperidin-4-yl)-3-cyclohexylmethylthio-2-((4R)-3-(3-hydroxypropyl)thiazolidin-4-ylcarbonylamino)propanamide,13)(2R)-N-(1-benzylpiperidin-4-yl)-3-cyclohexylnethylthio-2-((4R)-3-carboxymethylthiazolidin-4-ylcarbonylamino)propanamide,14)(2R)-N-(1-benzylpiperidin-4-yl)-3-cyclohexylmethylthio-2-(4R)-3-t-butoxycarbonyl-1,1-dioxothiazolidin-4-ylcarbonylamino)propanamide,15)(2R)-N-(1-benzylpiperidin-4-yl)-3-cyclohexylmethylthio-2-((4R)-3-t-butoxycarbonyl-1-oxothiazolidin-4-ylcarbonylamino)propanamide,16)(2R)-N-(1-benzylpiperidin-4-yl)-3-cyclohexylmethylthio-((4S)-3-t-butoxycarbonyl-2-oxooxazolidin-4-ylcarbonylamino)propanamide,17)(2R)-N-(1-benzylpiperidin-4-yl)-3-cyclohexylmethylthio-2-((4R)-3-hydroxymethylcarbonylthiazolidin-4-ylcarbonylamino)propanamide,18)(2R)-N-(1-benzylpiperidin-4-yl)-3-cyclohexylmethylthio-2-((4R)-3-(morpholin-4-ylcarbonylmethyl)thiazolidin-4-ylcarbonylamino)propanamide,19)(2R)-N-(1-benzylpiperidin-4-yl)-3-cyclohexylmethylthio-2-(4R)-3-(2-methoxyethoxycarbonyl)thiazolidin-4-ylcarbonylamino)propanamide,20)(2R)-N-(1-benzylpiperidin-4-yl)-3-cyclohexylmethylthio-2-((4R)-3-chloromethoxycarbonylthiazolidin-4-ylcarbonylamino)propanamide,21)(2R)-N-(1-benzylpiperidin-4-yl)-3-cyclohexylmethylthio-2-((4R)-3-(3,3-dimethylbutyryl)thiazolidin-4-ylcarbonylamino)propanamide,22)(2R)-N-(1-benzylpiperidin-4-yl)-3-cyclohexylmethylthio-2-((4R)-3-cyclopentylcarbonylthiazolidin-4-ylcarbonylamino)propanamide,23)(2R)-N-(1-benzylpiperidin-4-yl)-3-cyclohexylmethylthio-2-((4R)-3-benzoylthiazolidin-4-ylcarbonylamino)propanamide,24)(2R)-N-(1-benzylpiperidin-4-yl)-3-cyclohexylmethylthio-((4R)-3-(3,3-dimethyl-1,2-dioxobutyl)thiazolidin-4-ylcarbonylamino)propanamide,25)(2R)-N-(1-benzylpiperidin-4-yl)-3-cyclohexylmethylthio-((4R)-2,2,5,5-tetramethylthiazolidin-4-ylcarbonylamino)propanamide,26)(2R)-N-(1-benzylpiperidin-4-yl)-3-cyclohexylmethylthio-((2S)-1-t-butoxycarbonyl-4-oxopyrrolidin-2-ylcarbonylamino)propanamideor 27)(2R)-N-(1-benzylpiperidin-4-yl)-3-cyclohexylmethylthio-((2S,4R)-1-t-butoxycarbonyl-4-hydroxypyrrolidin-2-ylcarbonylamino)propanamideor non-toxic salts thereof.
 5. A compound according to claim 1 whichis 1)(2R)-N-(1-benzylpiperidin-4-yl)-3-cyclohexylmethylthio-2-((4R)-3-isopropylsulfonylthiazolidin-4-ylcarbonylamino)propanamide,2)(2R)-N-(1-benzylpiperidin-4-yl)-3-cyclohexylmethylthio-2-((4R)-3-cyclopentylsulfonylthiazolidin-4-ylcarbonylamino)propanamideor 3)(2R)-N-(1-benzylpiperidin-4-yl)-3-cyclohexylmethylthio-2-((4R)-3-isobutylsulfonylthiazolidin-4-ylcarbonylamino)propanamideor non-toxic salts thereof.
 6. A pharmaceutical composition comprising,as an active ingredient, an amino acid compound of the formula (I)depicted in claim 1, a non-toxic salt thereof, or a hydrate thereof, anda pharmaceutically acceptable carrier or diluent.
 7. A method fortreating a disease induced by an excessive release of neurotransmittersfrom N-type calcium channels selected from the group consisting ofcerebral infarct, transient ischemic attack, hypertension with stress,epilepsy, asthma and pollakiuria.
 8. A method for the treatment of paininduced by an excessive release of neurotransmitters from N-type calciumchannels, comprising administering to a host in need of such treatmentan effective amount of an amino acid compound of formula (I) depicted inclaim 1, a non-toxic salt thereof, or a hydrate thereof.